3.5 Immune Function in Cancer

cancer. Today we're going to be talking about immune function in cancer. And of course that's our third note that we talked about so far. So we started off with mental, emotional, spiritual health and biorhythms, then went on to talk about healthy microbiome balance and that's different microbiomes around the body and GI function and now we're coming on to balanced immune function. And of course immune function comes up in two different hallmarks of cancer and that's avoiding immune destruction and also tumour promoting inflammation. So it's really important because by working with this particular aspect we can be impacting two hallmarks of cancer. So what do we aim to do within this particular system? We may aim to decrease inflammation oxidative stress. and also support immune surveillance in a balance-specific anti-tumour response. And there's a significant role for TME or tumour microenvironment within that. And just to quickly remind you, a healthy immune system is meant to be detective, which means it should be able to detect any threat from within or outside the body. It should be internally regulated, so you should be able to regulate your immune response and be able to switch it off when you need to. And it should be restorative. and tolerant. So the idea of it is that we're meant to be able to restore balance to our immune system and tolerate things that are meant to be tolerated like self and innocuous antigens. So inflammation plays a huge role in all stages of cancer including initiation progression. Infection inflammation actually account for about 25% of cancer-causing factors globally and As we've spoken about a number of times before, there are well-known infection lengths like schistosomiasis and bladder cancer, helicobacter and gastric cancer, HPV, high-risk types and cervical cancer, EBV and nasopharyngeal carcinoma, and plenty of others. We also can see that there are pro-inflammatory factors from the environmental perspective that also play a role in cancer, and that's asbestos and air pollution and inflammatory diseases. So there's been well-established links between... diseases that drive chronic inflammation within an organ and cancer in the same organ. So for example there is a link between increased risk of colorectal cancer and a history of inflammatory bowel disease. Barrett's oesophagus is a pre-malignant stage for esophageal garden carcinoma and that's generated an inflammatory change in cell type in response to reflux, chronic gastric reflux. And also chronic hepatitis driven by HPV and M. HCV viruses and hepatitis viruses and HCC which is liver cancer. And there is a concept around that cancer is almost like a wound that never heals it's sort of this chronic inflammatory response it just keeps going without being turned off without achieving proper resolution proper control. So in terms of how inflammation might contribute to cancer initiation promotion we know that inflammation will generate oxidative stress and Reactive oxygen and nitrogen species damage DNA but also damage other macromolecules such as proteins or lipids, and that's like lipid peroxidation for example, and it results in their dysfunction. So one interesting thing to note is if you damage transferrin in an oxidative environment, it actually releases iron ions that then generate additional reactive oxygen species and then upregulate inflammation even further. So it's almost like a positive feed-forward loop. And epigenetics also plays a role, and that's sort of underappreciated, I think, in terms of having an indirect effect. So, for example, when we have high levels of pro-inflammatory cytokines such as IL-6, it can actually have an impact on the methylation. And I'll just cover this here quickly. So in a normal microenvironment, we have good antioxidant systems in place. We have raw scavengers. We have our normal internal antioxidant molecules. And. Our detoxification systems are working really well in terms of glutathione pathways etc. and we have a good balance between pro-oxidants and antioxidants, in which case we get normal gene expression and normal balance of methylation of genome. What happens in the inflammatory microenvironment is that inflammatory cells can secrete pro-inflammatory cytokines, for example interleukin-6, and that leads to activation of DNMT1 which is a methyl transferase. what happens is that it can then promote methylation in the promoter regions for specific genes that can shut down their gene expression. So you get hypermethylation in promoters for genes. tumour suppressor genes and global DNA hypomethylation. So there's an imbalance that then results in us turning off our tumour suppressor genes and decreasing microRNA expression for those that control oncogenes and therefore their activity can get increased and we can get a result in development of cancer. So it's important for us to think about Inflammation oxidative stress resulting from that as being drivers not only of direct damage to DNA, lipids and proteins, but also having an impact on the methylation of the genome. So key molecules, I'm going to only cover a few, there's lots and lots of molecules involved in inflammation and oxidative stress pathways, but particular ones that we like to talk about in terms of inflammation and cancer. cytokines, particularly IL-6, but IL-1 and TNF-alpha are also involved, COX-2 and downstream eicosanoids. And of course, the counterpoint to some of those prostaglandins and other more pro-inflammatory eicosanoids are things like resolution mediators, such as resolvins and moressins from omega-3. NF-kappa-B is, of course, one of the master regulators, and that's connected to NLRP3 inflammasome, which is a basically a factory for producing some of those pro-inflammatory cytokines. And there's a crosstalk between NF-kappa B and Nrf2, which is kind of the counter-regulator to that. And STAT3 is another important regulator. So when we're thinking about key molecules that you might want to read about in scientific papers that link inflammation and cancer, we need to think about IL-6, NF-kappa B and STAT3 in particular. So just as a reminder for NF-kappa B, we know that it's an inducible restriction factor that gets upregulated during times of increased inflammation oxidative stress and it in itself will then drive more inflammation effectively. It will upregulate production cytokines, chemokines and adhesion molecules and also has an impact on regulating cell cycle and reducing the propensity for the cells to go into operation. so producing anti-apoptotic factors, and can also produce various chemokines and cytokines that can result in upregulation of angiogenesis. So it's a significant driver in terms of the cancer and human microenvironment, really. In terms of inflammation and cancer progression, so we talked a little bit about initiation and how that might occur, but the other things we need to think about is actually how the how does it affect cancer progression and metastasis and invasion and the processes by which cancer spreads through the body. So cytokines actually activate the necessary pathways required by cancer stem cells to progress through EMT which is epithelial mesenchymal transition. That means you go from a static cell which is sitting there connected to your neighbours to a crawling cell that would like to escape and go off around the body. So it's important that cytokines secreted by those tumour-associated immune cells can actually promote that transition. And deregulation of COX-2 and PGE2 signalling pathways is associated with many tumours, particularly in colorectal cancer. And it's related, the upregulation of COX-2 and PGE2 production is related to metastasis and poor prognosis in patients with colorectal cancer. And also chemotherapy resistance. So it has a major impact on how the cancer progresses, but also whether we're going to be able to target it with therapy appropriately. The STAT3 signal, which we'll talk about in a minute in detail, is a major pathway for cancer inflammation because there's a very frequent activation of it in malignant cells, and it plays a key role in regulating many genes crucial for the inflammation in the tumor microenvironment. And we talked about IL-6 and the potential link to changing the methylation of the genome, but also it can promote haemogenesis by regulating all the different hallmarks of cancer. And signaling pathways that include apoptosis, cell survival and proliferation, angiogenesis, invasiveness and metastasis. So having good inflammation control is essential for us in terms of supporting patients with cancer. So STAT3, there's basically different STATs of different kinds, they all have a number and they have different function depending on that number. So STAT3 and to a less extent STAT5 are effectively pro-carcinogenic. They increase proliferation, survival, angiogenesis and metastasis in cancer and also inhibit anti-tumour immunity. The counterpoint to STAT3 and STAT5 is STAT1 and actually drives anti-tumor immune response. So it's a count regulator. So it means that we would want to be targeting quite specific stats to try and tip the balance to convert tumour-promoting inflammation to specific anti-tumour immune response. And the thing about STAT3 is that STAT3 is a bit of a master regulator which means that once it's activated to a significant degree, it will promote secretion of various signalling molecules including cytokines and growth receptors. that will then also activate STAT3. So you're getting this positive feedforward loop effectively. And the signaling that we're going to be discussing is that relevant to inflammation is IL-6, JAK, STAT3 signaling. So I'll talk you through the signaling pathway. But the other thing to be aware of is the other environmental inflammatory factors that will activate STAT3, such as, you know, excessive exposure to sunlight, specific pathogens or chemical carcinogens. which will also plug into that pathway. And STAT3 interacts with NF-kappa B, so again you've got that double whammy of inflammation and it's also in itself activated by things that are NF-kappa B regulated. So NF-kappa B can promote secretion of IL-6 and IL-6 in itself then will promote activation of STAT3. So it's quite a sort of close-knit inflammatory family. So if you think about this STAT3 pathway, so at the very top you can see IL-6 binds to its receptor, it dimerizes, which means it forms a little couple, a little pair, activates JAK, and that's Janus kinase, and JAK then goes off and talks to STAT3, puts a little phosphate on it called phosphorylation. STAT3 goes and finds another partner. So again, the STAT3s travel in pairs into the nucleus and then activate transcription of a number of different genes. including things that regulate the cell cycle and proliferation such as cyclin D and MYC and things that regulate apoptosis such as BCL2 and BACs and there's there are many things that it will be up regulating within that setting. So the other thing we've briefly touched on already is inflammation treatment resistance so not only does inflammation play a role in initiation promotion and progression of cancer it also impacts how resistant the cancer might be to treatment. So high levels of IL-6 actually protect cancer cells from the therapy-induced DNA damage and apoptosis by facilitating basically a counter signaling pathway. The other things to say is that actually the chronic inflammation in the tumor microenvironment has this persistent role in driving the survival and proliferation, keep going with angiogenesis and also immunosuppressing. the specific anti-tumor response within that environment. And let's not forget actually many therapies that we use in the cancer setting such as chemo and radiotherapy are pro-inflammatory as well so you can see how you can get stuck in a bit of a treatment resistance cycle. So in tumor microenvironment there's basically two things we look at. We would like to have part A, the tumor killing immune microenvironment. So we want to have good active NK cells, we want to have M1 macrophages, and we want to have a really robust CD8 response and a more Th1 driven response. And then we can actually get tumour control and tumour killing. The problem comes when the tumour becomes very clever and actually starts secreting all sorts of factors that will convert its tumour environment into more of a Th2 polarisation and actually starts being immunosuppressive and co-opting. all of these different cells around it to actually participate in its spread and metastasis. So in the immune suppressive microenvironment, you find MDSCs, and that's myeloid derived stem cells. They're the ones that can produce lots of angiogenic factors in response to the tumor talking to them. You get M2 macrophages rather than M1 macrophages, and they're more immunosuppressive, in fact. And you've got NK cells that are being suppressed by TGF beta. as one of the regulatory cytokines. So you find that actually what the tumor tries to do is instead of trying to promote the killing response, obviously it tries to hide and immunosuppress the tumor microenvironment and actually get it almost converted to its own cause and get it to promote different processes such as angiogenesis. So we want to try and repolarize it back to the tumor killing microenvironment. That's the goal. So... When do we assess the importance of immune system support in cancer? Pretty much always relevant to consider because it's going to be playing a role in a number of our patients. And the key clients, cancer, key aspects of the cancer. Cancer history, really, that we need to have a look at are recurrent infections. So if you have someone who just keeps having recurrent infections, particularly in the preceding sort of two to three years before getting cancer diagnosis, they just might tell you, I was just constantly ill. I was just every winter, I just picked up every cold going. Or doesn't ever get even a minor cold because it is normal to get an occasional mild cold. It's not normal to be completely laid out with it. but it's certainly normal to get an occasional immune response. Past medical history of autoimmune disease is very important because how we choose our intervention will very much depend on whether someone has a history of autoimmunity and it's important in the overall setting because actually it's very tricky balance because when we're trying to Immunomodulate, we need to keep that balance between not aggravating the immune system enough that it actually flares up the autoimmune disease. So combination of cancer and autoimmunity is a tricky one to strike the balance with. Vitamin D deficiency or unknown status for vitamin D is another thing to ask about. Gut immune axis, very important as we know already from the previous lecture. Antibiotics, other microbiome disrupting factors that you've learned about in... in our previous talk. And current treatment plan aspects will play a major role in you trying to figure out what you need to do to support this person. That's chemotherapy, radiotherapy or immunotherapy, for example. So in terms of tests, what do we do to assess inflammation immune balance? So in terms of assessing inflammation, Dr. Neysha likes to use her trifecta, which is CRP, SI and LDH. And total LDH you can get on the NHS, but it is harder to get. and it needs to be in the lab within eight hours so it needs to be a proper blood draw ideally. So ideally we would like to have LDH with isoenzymes and isoenzymes are basically different types of LDH that live in different tissues and can tell you something different in terms of are they associated with a malignant process or actually is it the LDH more relevant for other tissues that are nothing to do with malignancy for example. I tend to use either CRP or highly sensitive CRP depending on what my client has in terms of previous markers, ESR, ferritin, LDH. And I usually do run isoenzymes if I can get a proper blood draw. We do use lymphocyte to neutrophil to lymphocyte ratio, NLR, and ideally should be either 2.5 and I'll talk you through a couple of studies on that. And the up and coming marker that's been used in the last few years is PLR, so that's platelet to lymphocyte ratio. And we want to try and keep that under about 160. And study ranges use things like 170 to 200 is cut off. But it seems to be the most recent papers use about 160 as a cutoff for PLR. Always measure vitamin D levels. I know you will be, but this is essential for immune regulation. We might want to have a look at looking at oxidative stress markers, obviously not during chemotherapy or radiotherapy treatment, but say if we're looking maybe three to six months down the line, we want to see if actually we're trying to return to some kind of homeostasis and our antioxidant system's working well now. And we use things like 8-hydroxyde-DG and lipid peroxides, and that's really markers for any particular needs for water and fat-soluble antioxidants. SNPs will play a role. You will get them as a part of DNA health or Life Code GX nutrient profiles. And so we've got to remember, though, that SNPs are always, always about risk. They're always about potential risk, but they're not about current biochemical status. So do use them, but don't over rely on them either. And particular SNPs that are relevant to us within this setting is IL-1, IL-6 and TNF-alpha. And some profiles also have CRP SNPs. So NLR or neutrophil to lymphocyte ratio and cancer. There was a really big umbrella meta-analysis in 2020 that showed a very strong evidence of association between NLR and outcomes in a number of solid cancers and particularly also cancers treated with immunotherapy as well. So NLR cut-offs in various studies vary hugely, you know, from 1.9 to 5, which is a rather big difference. But most recent studies use cut-offs from just under 2.5, so it was one with 2.461, which is a very specific number, up to three. In a breast cancer meta-analysis in 2017, we found that when we used the median cut-off value for high NLI was around about three for the studies that were reporting an impact on overall survival, which is OS, and about 2.5, which was in the studies reporting DFS, which is disease-free survival outcomes. So I tend to go for 2.5 in my own practice because of that. And there were two other meta-analyses for breast cancer that shows that high NLR is associated with a diverse overall survival and disease-free survival in patients with breast cancer, and it's particularly impactful in triple negatives. So really, really important to get the NLR spot on. And studies are now combining NLRs, the neutrophil to lymphocyte ratio, with PLR, platelet to lymphocyte ratio, to assess immune balance. So in 2019 breast cancer study they actually looked at pathological complete response and that's PCR and whether that was actually impacted by immune status of cancer patients and they did find that definitely was impactful. So patients had low NLR and low PLR so the idea of that was that they didn't have a particularly pro-inflammatory tumour environment. They actually achieved a significantly higher rate of complete pathological response compared to those who had high NLR or high PLR, and therefore they're indicators of a more pro-inflammatory tumour microenvironment and more chronic inflammation in general, really. In 2019, there was a breast cancer meta-analysis which explored the role of platelet-to-lympho-situation predicting overall survival. And it definitely showed that elevated platelet to lymphocyte ratio was associated with a shorter disease-free survival. So it's an important marker for us that we can get very simply from full blood counts that are run on our patients and clients to be able to assess what's going on with their inflammatory status and what can we do for them to be able to address that. So the The other thing to think about is this just requires a full blood count, which is easy to do. And don't forget that it's far less relevant during chemotherapy because it will be skewing your NLR already because it might be preferentially down-regulating neutrophils. So it doesn't mean that someone has perfect NLR. It just means that actually they're being messed around with chemotherapy. So ideally you want to get a... the NPLI diagnosis and have a look at what they were like before that and then after something like chemotherapy or radiotherapy is completed then again you would want to look at full recovery to normal ratio that's that's really important. LDH so why on earth do we measure LDH in terms of thinking about inflammation in tumor microenvironment because it's actually a metabolic marker so the reason we do it is because LDH and the resulting lactate is really the metabolic link between tumor cells and tumor microenvironment. So lactate is produced as a result of the Warburg effect in the tumor cells because they actually undergo aerobic glycolysis. But it's not only produced as a byproduct of the metabolism, it's also a key molecule in carcinogenesis and tumor immune evasion. It's an immune suppressant in a tumor microenvironment. So apart from being a marker of the metabolic status, it has a significant prognostic predictor of overall survival, it's really important for us. So, and the other things to think about is that serum LDH can also serve as a predictive response to chemotherapy. So in TNBC for example, I use it quite a lot just because there's been more data within that, but there was a strong association found between serum LDH levels, high number of metastatic sites and poor prognosis. And there was a reduced progression-free survival and predicted poor overall survival and poor response to chemotherapy. So we want to make sure that LDH is down to normal levels as much as we can do. And this doesn't just extend to breast cancer. There have been a number of different studies in various other solid tumours. Actually LDH is also used in blood malignancies as well as part of their markers. So lactate is important because when the tumour associated immune cells produce lactate, they will not only acidify the tumour microenvironment and cause it to become more immunosuppressive, but it also facilitates... metastatic dissemination and therapy resistance so it is important for us to keep an eye on that LDH if we can. So in terms of how we're going to address this now we've tested we've done our CRP ESR hopefully got an LDH looked at some vitamin D and some of the other markers that we talked about What do we want to do about it now? And the key thing is, as I always say, don't forget to look at the root causes and factors in the chronic inflammation immune dysregulation. So sometimes people will assume that it's normal to have really high inflammatory markers when you have cancer, and metastatic cancer in particular. And actually it's slightly turned around on its head. We need to be able to try and get that inflammation down so that we can try and have better response to treatment. and promote better immune control within our cancer clients. So the key thing that you want to look about is what's causing and driving this chronic inflammation. Food is really important to assess, as we know. So diet like standard American diet or standard British diet with its poor omega-6 to omega-3 ratio, toxic oxidized fats, high saturated fat and low fiber promoting dysbiosis, which will play into inflammation. Acrylamide from highly processed. carb foods cooked at high temperatures, high sugar and that's age-rage interactions driving inflammation, poor dietary antioxidant intake including all the phytonutrients, pesticides and additives and nutritional deficiencies and that includes vitamin D and again a number of other nutrients that we know are important for healthy immune function and immune regulation. Sometimes if you have someone who's you're not sure about the omega-6 to omega-3 ratio then it's very quite useful to do a proper blood spot on them and have a look at their fat ratios. Dysbiosis can drive chronic inflammation, it's a factor I see play a massive role in many of my cancer clients and infections, toxins, drugs and alcohol, stress, trauma and sleep disruption are pro-inflammatory and lack of appropriate physical activity or excessive physical activity without adequate rest. So they are all factors to consider. when we're looking at why is someone inflamed, why does someone have an elevated CRP or ESR or other markers. So interventions. Interventions particularly are split here into things we want to do from the inflammatory point of view and things that we might want to do to try and support a specific anti-tumor response. So always start with lifestyle and inflammation. You would have heard from me a number of times, but I will reiterate it. So your anti-inflammatory whole food diet. with correct omega-3 to omega-6 ratio, high phytonutrient index from vegetables, low sugar fruit, particularly polyphenol rich berries, herbs and spices, appropriate fasting, sleep, movement and stress management. So particularly attention in terms of herbs and spices are we know all about turmeric, we've all heard about it, particularly consumed with fat plus or minus black pepper depending on how good the gut is at that point. and how irritated the upper GI tract is because I wouldn't use it if someone has castritis for example. Ginger, rosemary, saffron, chili, all sorts but most herbs and spices basically contain antioxidant anti-inflammatory compounds so for example parsley contains very valuable flavonoid compounds called epigenin, quercetin and luteolin. So pretty much the more the merrier and the more diversity and variety you can get the better. It's not about overdoing one thing, so just overdoing the turmeric, but actually it's all about just trying to have a balance and a mix of the different compounds. Herbal teas with anti-inflammatory and antioxidant effects, there are again plenty of them, most of them have an anti-inflammatory and antioxidant effect, but green tea, gynostemma, tulsi and ginger are particularly worthwhile mentioning. Intermittent fasting or caloric restriction is anti-inflammatory, and the latter is obviously less popular. We do tend to opt for intermittent fasting. Don't overdo the fasting if the patient is losing weight or has a low BMI. It's not appropriate for BMI on day 18. There are different regimes, of course, we know about fasting mimicking diet, extended overnight fasts of 13 to 14 hours, 16-8 time restricted feeding or fasting days. So it just depends on your individual clinical assessment of what you think your client will be able to manage and also how metabolically dysregulated they are. So treat the root cause always, so we're not just going to be slapping on anti-inflammatory interventions because we need to actually unplug the inflammation at its cause. So we're not going to be just mopping the floor, you need to turn off the tap. So for example, treat the dysbiosis, if there are infections driving it, if there's anything else driving this inflammation, you need to treat it, remove it or tackle it in some way. And as I said, it's often assumed that high inflammatory markers are a consequence of cancer, but it's not always the case and you do need to look at other factors. So specific interventions we might consider, we might want to look at omega-3 and vitamin D is just the basics, you know D3 ideally would be combined with K2 unless you're on anti-oculants like warfarin for example. You would want to use antioxidants as appropriate, so always food first, don't forget that's where we should be deriving most of our antioxidants and the widest variety of phytogenes you can get. The one antioxidant I will occasionally use in combination with Active therapy, active treatments, tocotrienols, they can be very useful. But no other high-dose antioxidant supplementation during chemotherapy until proven otherwise. And of course, other specific antioxidants that we know in specific cases are just like a prostate cancer. But again, food first still. I would normally get people to have one or two tablespoons of tomato puree with some extra virgin olive oil instead of trying to shovel a whole ton of lycopene down them. Most commonly used supplements that we use in this particular case, and again there are plenty more, this is just a small selection that have some data in cancer and that people have used clinically, but it is just a tiny bit that we can have a look at. Curcumin, obviously we know that's one of the most popular ones for a very good reason, but caution in significantly elevated LFTs, if you do find liver function enzymes are really going off, then you will. might want to decrease your curcumin dose significantly because it can make people feel really quite a lot more nauseous. Black cumin seed and agela sativa is a rich source of thymoquinone and is a beautiful anti-inflammatory and immunomodulator. I use it a lot. Willow bark is herbal aspirin basically in the Cox inhibitor so that's a context in which we use that but much kinder on the GI lining. Specific polyphenols is appropriate, resveratrol, EGCG, etc. There's plenty of those and some people will use CBD oil as well, which has multiple different mechanisms of action to it. So tocotrienols in cancer, so one antioxidant where actually you can combine it with certain therapies, not necessarily every single therapy, but it might be useful in some active cancer treatment. So gamma and delta tocotrienols specifically. have the highest anti-cancer activity and target a whole number of pathways. For example, inhibiting cell cycle, induction of apoptosis and autophagy, inhibition of invasion metastasis and angiogenesis. And actually what's really interesting is that tocotrienols appear to synergize with both pharmaceutical antitumor agents such as chemotherapy, statins and some of the other targeted therapies or natural compounds again with EGCG, resveratrol, ferulic acid for example. So It's a really important tool that's very useful for us. And it's important that we use gamma and delta tocotrienols, not just in general vitamin E. As we know, most vitamin E in supplements is not such a great quality and relies heavily on alpha-tocopherol, for example, instead of the tocotrienols, which are the truly valuable compounds. We've got to remember that tocotrienols and tocopherols often compete for absorption. So actually it would be better to give tocotrienols alone rather than in combined formulae. There was a phase 2 trial of bevacizumab, which is an anti-VEGF drug, combined with tocotrienols in chemotherapy of refractory ovarian cancer. And what was amazing in that is the rate of disease stabilisation was 70%. So that's 70% of those patients with ovarian cancer which did not respond to chemotherapy stabilised on... Bevacizumab with tocotrienols with very low toxicity and the median progression free survival was about seven months and overall survival was about 11 months and this is late stage ovarian cancer and this is high compared to the current literature so it was significantly synergistic in this combination certainly something to consider and there are multiple studies mainly in cells and animals that showing effects on NF-kappa b synergy with the different chemotherapy agents and reversal of multi-drug resistant, as well as inhibition of the stemness, which is a stem cell property in cancer stem cells. And a number of things that we might want to consider about when thinking about JAK-STAT pathway, which we talked about as a really key driver, you know, talking back to the beginning of the lecture where we said IL-6. kind of JAK-STAT and then you also have the other interaction with NF-kappa-B as well. So number of different compounds is a huge amount to choose from that interferes with things in different components of this JAK-STAT pathway from the top to the bottom and there are a number of them that act at specific at several different points so for example EGCG acts at the point of the top bit as well as the bottom bit in terms of the target genes. You also find that resveratrol and curcumin will act in a number of different parts of the pathway. Let's talk a little bit about polyphenols because polyphenols have significant anti-inflammatory and antioxidant actions. And I think it's important for us to get a bit of clarity about what polyphenols actually are. So polyphenols include two different groups. They're plant-derived compounds that include two different groups of chemicals, non-flavonoids and flavonoids. So non-flavonoids chemical compounds that exist within plants include HBA and HCA and still beans. And they're the ones we hear quite a lot about, and that's terastilbene and resveratrol in particular. Then we look at flavonoids in a number of different groups. Flavanols, such as EGCG, that's a very popular one, of course, as we know, within cancer support. Flavanols, and that's quercetin, camphorol, and muricetin. Isoflavones as we know in terms of being soy derived, genistein, diazine, anthocyanidins and number of those around and flavonoids and that's hesperidin and noreginin and they're really quite a lot more enriched in the citrus fruit in particular. So there are some specific antioxidant flavonoids that are useful in the context of cancer for multiple different effects but particularly things like EGCG, genistein, diazine are used quite a lot. quercetin, apigenin, christian and luteolin and many many others. The above are just the most studied and I will share a paper on the learning platform that talks you through all the various compounds and kind of where they come from and how they might be helpful and some of the evidence around those. So I want to just highlight a few specific whole foods that as well as plant extracts that can be quite useful. To use and see ginger is anti-inflammatory, it also has anti-proliferative and anti-tumor activities and what we do know is a ginger extract in six gingerol which is one of the compounds found in ginger they actually they activate Nrf2, they decrease activation of TNF alpha, ROS and F-kappa B and COX-2 pathways and there are different options for using ginger you know always use it in food ginger decoction and I find that generally The herbs, leafy herbs in general, we think about in herbalism are better brewed as tea, but roots really need to be decocted, which means actually boiled in boiling water for a little bit of time to be able to extract all the different compounds within it. And we want to try and keep the lid on so we don't let too many of the lovely volatile chemicals escape, so sort of try and do it with a partially sharp lid when you do the decoction. So plain tea, plain ginger tea is fine, it doesn't achieve maximal extraction so ideally you'd want to decoct your grated ginger for about 10 minutes if possible and we of course can also use it as a supplement. Not forgetting the fact that also ginger can have other effects in terms of being supportive to the gut and reducing nausea so a number of ways of using it to support our clients with cancer. Curcumin, I mean what doesn't it do really should be the question. So, of course, within this particular talk, we are going to remind ourselves that curcumin has been demonstrated to have a significant anti-inflammatory effect through multiple different signaling pathways, including NF-kappa B, JAK-STAT, and TGF-beta pathways. And so it also activates, of course, as we know, the apoptotic pathways and inhibits inflammation, geogenesis, and metastasis. And a number of things that we'll also target that are to do with... Apoptosis is things to do with p53, RAS which is more about driving cell proliferation, PA3K and PKB which are involved in the metabolic side of things, and beta-catenin and Wnt and mTOR which are involved in both metabolic but also the stem cell pathways. The other things to say is that curcumin of course goes broader than that and also exerts beneficial effects on cancer treatment related toxicities such as kidney toxicity, cardiotoxicity and toxicity to the nervous system. So it's a very useful multi-agent to use in a number of different settings. In terms of which curcumin, I mean, there are so many formulations in the market. At one point, I will do a review which one are the most kind of bioavailable and dosing, etc. But what we do know is that Lipocirc and Meriva have been studied in cancer specifically. And Meriva is a... Lethizynized formulation of curcumin for better bioavailability and you can get a soy-free version as well. So just a quick reminder the fact that curcumin has been found to work alongside chemotherapies in a number of different settings including prostate cancer, liver cancer, gastric cancer, blood and colorectal. So something to keep in mind, the fact that it's a compound that has been used alongside some of the active chemotherapy drugs. And there are many, many ongoing trials with curcumin. Here's just a tiny, tiny selection, but there are a number of them and you can see they're being used in combination with chemotherapy quite a lot of the time or after significant interventions like prostatectomy. So it's really important and even in the prevention setting there's actually a trial for nano emulsion of curcumin for obesity, inflammation, breast cancer prevention so it'd be interesting to see where that shows up. So if you are trying to use it within a specific setting just put curcumin and whatever drug of choice your client is on in PubMed and see if there been any studies on the combination because it might be useful to you to have that as a backup. Black cumin seed or Nigella sativa and inflammation cancer. Thymoquinone is a major active constituent of black cumin seed and has a huge number of different effects. There are a number of ways in which thymoquinone mediates cancer activity. It will affect p53, NF-kB, STAT3 which we talked about as major pro-inflammatory drivers. It will also affect the nutrient metabolic sensing mechanisms and it will affect the pro-growth and pro-proliferation signaling pathways such as PI3K and ACT. So you can see a number of different molecules are being affected here and there's also early evidence around enhancement of NK cell-mediated cytotoxicity so maybe instead of an anti-inflammatory it's actually more of an immunomodulator something like medicinal mushrooms. So talking about medicinal mushrooms, we are now moving on from just doing anti-inflammatory interventions to thinking about supporting anti-tumor response. And so specifically, we're going to talk about medicinal mushrooms PSK and two other mushroom products licensed in the Far East for supportive care during cancer treatment. There's astragalus membranaceus, which is a wonderful TCM herb that's used to support systemic immunity and ameliorate immunosuppression. It actually activates the... T-cell tumour kill function and M1 macrophages in the tumour microenvironment. And there's some very early studies in andrographis as well. Medically, of course, they use immunotherapy, and we know that particularly with the checkpoint inhibitors, we need a healthy gut microbiome, and they do carry a risk of new onset autoimmunity, which is tricky. Ideally, from the medical point of view, the medics would minimise steroids unless absolutely necessary because you're suppressing tumour-specific immunity anyway. And you might want to consider gastro-resistant aspirin, particularly in colorectal cancer. So that's really with regard to Cox inhibition. And there's a caution with NSAIDs. Again, NSAIDs are quite overused within the cancer setting. And while they do have some beneficial effects, there are other ways of inhibiting the same pathways without risking GI toxicity and kidney toxicity from NSAID overuse. And of course the other interventions are out of scope for nutrition professionals but you can also refer to for mistletoe to optimize quality of life and support immune system balance and LDN is also used off-label for immunomodulation. So mistletoe therapy part of the way it works is immunomodulatory lectins and a number of different brands like Iscador, Helixor and Obnobufraxine and it must be at minimum subcutaneous and there's no proper really good data on oral even though Royal London Hospital for Integrative Medicine insists on using mostly oral but actually having done an evidence review I see very little evidence for this but much better evidence for subcutaneous injection and it's offered by a number of different integrative medicine doctors and there's a major centre in Scotland called Camp Hill Wellbeing which is well worth referring to. It's not always appropriate straight away. It's one of those things whereby people just get thrown onto mistletoe but when you have very high inflammatory markers, when I have some of my patients who have CRPs of in excess of 150 or 200 or someone's ESI is 80, you really don't want to be waiting in there with mistletoe first. You want to try and reduce the inflammation a bit before you get mistletoe started or starting at a very very low doses. And it's not appropriate if you've got active brain mets with cerebral edema and there's room for argument for whether you can do it in other cases after treatment for the metastases. In terms of summary, just to remind you that our key goals are to decrease inflammation, oxidative stress, support immune surveillance and a balanced specific anti-tumor response. and that's trying to get that Th1 polarisation away from the Th2 in immunosuppressive environment the tumour is trying to generate. For assessment, at minimum, get neutrophil to lymphocyte ratio, platelet to lymphocyte ratio, easy to do from full blood count, vitamin D, CRP and ferritin, and if you can get it, try and add ESI and LDH because they're useful. Look at root causes appropriate excess oxidative stress if you're looking at three to six months post active therapy and review SNPs in the wider panels just to see whether the person is more likely to exhibit an exaggerated inflammatory response. Support of course we talked about the anti-inflammatory whole food based diet rich in phytonutrients. We do need to incorporate dietary mushrooms you'll get a new lecture on mushrooms shortly and of course the herbs and spices. Anti-inflammatory other lifestyle interventions combining nutrition with fasting, appropriate movements, supplementation, stress management, don't forget to check your interactions with your supplements, and supporting immune surveillance and anti-tumor responses for us will include things like medicinal mushrooms and astragalus. We can argue about whether nigella sativa or black cumin seed belongs in this category as well, and consider referral for other therapies if more support is needed. Thank you very much for listening.

And of course immune function comes up in two different hallmarks of cancer and that's avoiding immune destruction and also tumour promoting inflammation. So it's really important because by working with this particular aspect we can be impacting two hallmarks of cancer. So what do we aim to do within this particular system? We may aim to decrease inflammation oxidative stress. and also support immune surveillance in a balance-specific anti-tumour response.

And there's a significant role for TME or tumour microenvironment within that. And just to quickly remind you, a healthy immune system is meant to be detective, which means it should be able to detect any threat from within or outside the body. It should be internally regulated, so you should be able to regulate your immune response and be able to switch it off when you need to. And it should be restorative. and tolerant.

So the idea of it is that we're meant to be able to restore balance to our immune system and tolerate things that are meant to be tolerated like self and innocuous antigens. So inflammation plays a huge role in all stages of cancer including initiation progression. Infection inflammation actually account for about 25% of cancer-causing factors globally and As we've spoken about a number of times before, there are well-known infection lengths like schistosomiasis and bladder cancer, helicobacter and gastric cancer, HPV, high-risk types and cervical cancer, EBV and nasopharyngeal carcinoma, and plenty of others. We also can see that there are pro-inflammatory factors from the environmental perspective that also play a role in cancer, and that's asbestos and air pollution and inflammatory diseases. So there's been well-established links between...

diseases that drive chronic inflammation within an organ and cancer in the same organ. So for example there is a link between increased risk of colorectal cancer and a history of inflammatory bowel disease. Barrett's oesophagus is a pre-malignant stage for esophageal garden carcinoma and that's generated an inflammatory change in cell type in response to reflux, chronic gastric reflux.

And also chronic hepatitis driven by HPV and M. HCV viruses and hepatitis viruses and HCC which is liver cancer. And there is a concept around that cancer is almost like a wound that never heals it's sort of this chronic inflammatory response it just keeps going without being turned off without achieving proper resolution proper control.

So in terms of how inflammation might contribute to cancer initiation promotion we know that inflammation will generate oxidative stress and Reactive oxygen and nitrogen species damage DNA but also damage other macromolecules such as proteins or lipids, and that's like lipid peroxidation for example, and it results in their dysfunction. So one interesting thing to note is if you damage transferrin in an oxidative environment, it actually releases iron ions that then generate additional reactive oxygen species and then upregulate inflammation even further. So it's almost like a positive feed-forward loop. And epigenetics also plays a role, and that's sort of underappreciated, I think, in terms of having an indirect effect.

So, for example, when we have high levels of pro-inflammatory cytokines such as IL-6, it can actually have an impact on the methylation. And I'll just cover this here quickly. So in a normal microenvironment, we have good antioxidant systems in place. We have raw scavengers.

We have our normal internal antioxidant molecules. And. Our detoxification systems are working really well in terms of glutathione pathways etc. and we have a good balance between pro-oxidants and antioxidants, in which case we get normal gene expression and normal balance of methylation of genome. What happens in the inflammatory microenvironment is that inflammatory cells can secrete pro-inflammatory cytokines, for example interleukin-6, and that leads to activation of DNMT1 which is a methyl transferase.

what happens is that it can then promote methylation in the promoter regions for specific genes that can shut down their gene expression. So you get hypermethylation in promoters for genes. tumour suppressor genes and global DNA hypomethylation.

So there's an imbalance that then results in us turning off our tumour suppressor genes and decreasing microRNA expression for those that control oncogenes and therefore their activity can get increased and we can get a result in development of cancer. So it's important for us to think about Inflammation oxidative stress resulting from that as being drivers not only of direct damage to DNA, lipids and proteins, but also having an impact on the methylation of the genome. So key molecules, I'm going to only cover a few, there's lots and lots of molecules involved in inflammation and oxidative stress pathways, but particular ones that we like to talk about in terms of inflammation and cancer. cytokines, particularly IL-6, but IL-1 and TNF-alpha are also involved, COX-2 and downstream eicosanoids. And of course, the counterpoint to some of those prostaglandins and other more pro-inflammatory eicosanoids are things like resolution mediators, such as resolvins and moressins from omega-3.

NF-kappa-B is, of course, one of the master regulators, and that's connected to NLRP3 inflammasome, which is a basically a factory for producing some of those pro-inflammatory cytokines. And there's a crosstalk between NF-kappa B and Nrf2, which is kind of the counter-regulator to that. And STAT3 is another important regulator. So when we're thinking about key molecules that you might want to read about in scientific papers that link inflammation and cancer, we need to think about IL-6, NF-kappa B and STAT3 in particular.

So just as a reminder for NF-kappa B, we know that it's an inducible restriction factor that gets upregulated during times of increased inflammation oxidative stress and it in itself will then drive more inflammation effectively. It will upregulate production cytokines, chemokines and adhesion molecules and also has an impact on regulating cell cycle and reducing the propensity for the cells to go into operation. so producing anti-apoptotic factors, and can also produce various chemokines and cytokines that can result in upregulation of angiogenesis. So it's a significant driver in terms of the cancer and human microenvironment, really. In terms of inflammation and cancer progression, so we talked a little bit about initiation and how that might occur, but the other things we need to think about is actually how the how does it affect cancer progression and metastasis and invasion and the processes by which cancer spreads through the body.

So cytokines actually activate the necessary pathways required by cancer stem cells to progress through EMT which is epithelial mesenchymal transition. That means you go from a static cell which is sitting there connected to your neighbours to a crawling cell that would like to escape and go off around the body. So it's important that cytokines secreted by those tumour-associated immune cells can actually promote that transition.

And deregulation of COX-2 and PGE2 signalling pathways is associated with many tumours, particularly in colorectal cancer. And it's related, the upregulation of COX-2 and PGE2 production is related to metastasis and poor prognosis in patients with colorectal cancer. And also chemotherapy resistance.

So it has a major impact on how the cancer progresses, but also whether we're going to be able to target it with therapy appropriately. The STAT3 signal, which we'll talk about in a minute in detail, is a major pathway for cancer inflammation because there's a very frequent activation of it in malignant cells, and it plays a key role in regulating many genes crucial for the inflammation in the tumor microenvironment. And we talked about IL-6 and the potential link to changing the methylation of the genome, but also it can promote haemogenesis by regulating all the different hallmarks of cancer.

And signaling pathways that include apoptosis, cell survival and proliferation, angiogenesis, invasiveness and metastasis. So having good inflammation control is essential for us in terms of supporting patients with cancer. So STAT3, there's basically different STATs of different kinds, they all have a number and they have different function depending on that number. So STAT3 and to a less extent STAT5 are effectively pro-carcinogenic.

They increase proliferation, survival, angiogenesis and metastasis in cancer and also inhibit anti-tumour immunity. The counterpoint to STAT3 and STAT5 is STAT1 and actually drives anti-tumor immune response. So it's a count regulator.

So it means that we would want to be targeting quite specific stats to try and tip the balance to convert tumour-promoting inflammation to specific anti-tumour immune response. And the thing about STAT3 is that STAT3 is a bit of a master regulator which means that once it's activated to a significant degree, it will promote secretion of various signalling molecules including cytokines and growth receptors. that will then also activate STAT3.

So you're getting this positive feedforward loop effectively. And the signaling that we're going to be discussing is that relevant to inflammation is IL-6, JAK, STAT3 signaling. So I'll talk you through the signaling pathway.

But the other thing to be aware of is the other environmental inflammatory factors that will activate STAT3, such as, you know, excessive exposure to sunlight, specific pathogens or chemical carcinogens. which will also plug into that pathway. And STAT3 interacts with NF-kappa B, so again you've got that double whammy of inflammation and it's also in itself activated by things that are NF-kappa B regulated. So NF-kappa B can promote secretion of IL-6 and IL-6 in itself then will promote activation of STAT3. So it's quite a sort of close-knit inflammatory family.

So if you think about this STAT3 pathway, so at the very top you can see IL-6 binds to its receptor, it dimerizes, which means it forms a little couple, a little pair, activates JAK, and that's Janus kinase, and JAK then goes off and talks to STAT3, puts a little phosphate on it called phosphorylation. STAT3 goes and finds another partner. So again, the STAT3s travel in pairs into the nucleus and then activate transcription of a number of different genes.

including things that regulate the cell cycle and proliferation such as cyclin D and MYC and things that regulate apoptosis such as BCL2 and BACs and there's there are many things that it will be up regulating within that setting. So the other thing we've briefly touched on already is inflammation treatment resistance so not only does inflammation play a role in initiation promotion and progression of cancer it also impacts how resistant the cancer might be to treatment. So high levels of IL-6 actually protect cancer cells from the therapy-induced DNA damage and apoptosis by facilitating basically a counter signaling pathway. The other things to say is that actually the chronic inflammation in the tumor microenvironment has this persistent role in driving the survival and proliferation, keep going with angiogenesis and also immunosuppressing. the specific anti-tumor response within that environment.

And let's not forget actually many therapies that we use in the cancer setting such as chemo and radiotherapy are pro-inflammatory as well so you can see how you can get stuck in a bit of a treatment resistance cycle. So in tumor microenvironment there's basically two things we look at. We would like to have part A, the tumor killing immune microenvironment.

So we want to have good active NK cells, we want to have M1 macrophages, and we want to have a really robust CD8 response and a more Th1 driven response. And then we can actually get tumour control and tumour killing. The problem comes when the tumour becomes very clever and actually starts secreting all sorts of factors that will convert its tumour environment into more of a Th2 polarisation and actually starts being immunosuppressive and co-opting. all of these different cells around it to actually participate in its spread and metastasis. So in the immune suppressive microenvironment, you find MDSCs, and that's myeloid derived stem cells.

They're the ones that can produce lots of angiogenic factors in response to the tumor talking to them. You get M2 macrophages rather than M1 macrophages, and they're more immunosuppressive, in fact. And you've got NK cells that are being suppressed by TGF beta. as one of the regulatory cytokines. So you find that actually what the tumor tries to do is instead of trying to promote the killing response, obviously it tries to hide and immunosuppress the tumor microenvironment and actually get it almost converted to its own cause and get it to promote different processes such as angiogenesis.

So we want to try and repolarize it back to the tumor killing microenvironment. That's the goal. So... When do we assess the importance of immune system support in cancer?

Pretty much always relevant to consider because it's going to be playing a role in a number of our patients. And the key clients, cancer, key aspects of the cancer. Cancer history, really, that we need to have a look at are recurrent infections. So if you have someone who just keeps having recurrent infections, particularly in the preceding sort of two to three years before getting cancer diagnosis, they just might tell you, I was just constantly ill.

I was just every winter, I just picked up every cold going. Or doesn't ever get even a minor cold because it is normal to get an occasional mild cold. It's not normal to be completely laid out with it.

but it's certainly normal to get an occasional immune response. Past medical history of autoimmune disease is very important because how we choose our intervention will very much depend on whether someone has a history of autoimmunity and it's important in the overall setting because actually it's very tricky balance because when we're trying to Immunomodulate, we need to keep that balance between not aggravating the immune system enough that it actually flares up the autoimmune disease. So combination of cancer and autoimmunity is a tricky one to strike the balance with.

Vitamin D deficiency or unknown status for vitamin D is another thing to ask about. Gut immune axis, very important as we know already from the previous lecture. Antibiotics, other microbiome disrupting factors that you've learned about in... in our previous talk.

And current treatment plan aspects will play a major role in you trying to figure out what you need to do to support this person. That's chemotherapy, radiotherapy or immunotherapy, for example. So in terms of tests, what do we do to assess inflammation immune balance?

So in terms of assessing inflammation, Dr. Neysha likes to use her trifecta, which is CRP, SI and LDH. And total LDH you can get on the NHS, but it is harder to get. and it needs to be in the lab within eight hours so it needs to be a proper blood draw ideally.

So ideally we would like to have LDH with isoenzymes and isoenzymes are basically different types of LDH that live in different tissues and can tell you something different in terms of are they associated with a malignant process or actually is it the LDH more relevant for other tissues that are nothing to do with malignancy for example. I tend to use either CRP or highly sensitive CRP depending on what my client has in terms of previous markers, ESR, ferritin, LDH. And I usually do run isoenzymes if I can get a proper blood draw.

We do use lymphocyte to neutrophil to lymphocyte ratio, NLR, and ideally should be either 2.5 and I'll talk you through a couple of studies on that. And the up and coming marker that's been used in the last few years is PLR, so that's platelet to lymphocyte ratio. And we want to try and keep that under about 160. And study ranges use things like 170 to 200 is cut off. But it seems to be the most recent papers use about 160 as a cutoff for PLR. Always measure vitamin D levels.

I know you will be, but this is essential for immune regulation. We might want to have a look at looking at oxidative stress markers, obviously not during chemotherapy or radiotherapy treatment, but say if we're looking maybe three to six months down the line, we want to see if actually we're trying to return to some kind of homeostasis and our antioxidant system's working well now. And we use things like 8-hydroxyde-DG and lipid peroxides, and that's really markers for any particular needs for water and fat-soluble antioxidants. SNPs will play a role. You will get them as a part of DNA health or Life Code GX nutrient profiles.

And so we've got to remember, though, that SNPs are always, always about risk. They're always about potential risk, but they're not about current biochemical status. So do use them, but don't over rely on them either.

And particular SNPs that are relevant to us within this setting is IL-1, IL-6 and TNF-alpha. And some profiles also have CRP SNPs. So NLR or neutrophil to lymphocyte ratio and cancer.

There was a really big umbrella meta-analysis in 2020 that showed a very strong evidence of association between NLR and outcomes in a number of solid cancers and particularly also cancers treated with immunotherapy as well. So NLR cut-offs in various studies vary hugely, you know, from 1.9 to 5, which is a rather big difference. But most recent studies use cut-offs from just under 2.5, so it was one with 2.461, which is a very specific number, up to three.

In a breast cancer meta-analysis in 2017, we found that when we used the median cut-off value for high NLI was around about three for the studies that were reporting an impact on overall survival, which is OS, and about 2.5, which was in the studies reporting DFS, which is disease-free survival outcomes. So I tend to go for 2.5 in my own practice because of that. And there were two other meta-analyses for breast cancer that shows that high NLR is associated with a diverse overall survival and disease-free survival in patients with breast cancer, and it's particularly impactful in triple negatives.

So really, really important to get the NLR spot on. And studies are now combining NLRs, the neutrophil to lymphocyte ratio, with PLR, platelet to lymphocyte ratio, to assess immune balance. So in 2019 breast cancer study they actually looked at pathological complete response and that's PCR and whether that was actually impacted by immune status of cancer patients and they did find that definitely was impactful. So patients had low NLR and low PLR so the idea of that was that they didn't have a particularly pro-inflammatory tumour environment.

They actually achieved a significantly higher rate of complete pathological response compared to those who had high NLR or high PLR, and therefore they're indicators of a more pro-inflammatory tumour microenvironment and more chronic inflammation in general, really. In 2019, there was a breast cancer meta-analysis which explored the role of platelet-to-lympho-situation predicting overall survival. And it definitely showed that elevated platelet to lymphocyte ratio was associated with a shorter disease-free survival.

So it's an important marker for us that we can get very simply from full blood counts that are run on our patients and clients to be able to assess what's going on with their inflammatory status and what can we do for them to be able to address that. So the The other thing to think about is this just requires a full blood count, which is easy to do. And don't forget that it's far less relevant during chemotherapy because it will be skewing your NLR already because it might be preferentially down-regulating neutrophils.

So it doesn't mean that someone has perfect NLR. It just means that actually they're being messed around with chemotherapy. So ideally you want to get a...

the NPLI diagnosis and have a look at what they were like before that and then after something like chemotherapy or radiotherapy is completed then again you would want to look at full recovery to normal ratio that's that's really important. LDH so why on earth do we measure LDH in terms of thinking about inflammation in tumor microenvironment because it's actually a metabolic marker so the reason we do it is because LDH and the resulting lactate is really the metabolic link between tumor cells and tumor microenvironment. So lactate is produced as a result of the Warburg effect in the tumor cells because they actually undergo aerobic glycolysis. But it's not only produced as a byproduct of the metabolism, it's also a key molecule in carcinogenesis and tumor immune evasion. It's an immune suppressant in a tumor microenvironment.

So apart from being a marker of the metabolic status, it has a significant prognostic predictor of overall survival, it's really important for us. So, and the other things to think about is that serum LDH can also serve as a predictive response to chemotherapy. So in TNBC for example, I use it quite a lot just because there's been more data within that, but there was a strong association found between serum LDH levels, high number of metastatic sites and poor prognosis. And there was a reduced progression-free survival and predicted poor overall survival and poor response to chemotherapy. So we want to make sure that LDH is down to normal levels as much as we can do.

And this doesn't just extend to breast cancer. There have been a number of different studies in various other solid tumours. Actually LDH is also used in blood malignancies as well as part of their markers. So lactate is important because when the tumour associated immune cells produce lactate, they will not only acidify the tumour microenvironment and cause it to become more immunosuppressive, but it also facilitates... metastatic dissemination and therapy resistance so it is important for us to keep an eye on that LDH if we can.

So in terms of how we're going to address this now we've tested we've done our CRP ESR hopefully got an LDH looked at some vitamin D and some of the other markers that we talked about What do we want to do about it now? And the key thing is, as I always say, don't forget to look at the root causes and factors in the chronic inflammation immune dysregulation. So sometimes people will assume that it's normal to have really high inflammatory markers when you have cancer, and metastatic cancer in particular. And actually it's slightly turned around on its head.

We need to be able to try and get that inflammation down so that we can try and have better response to treatment. and promote better immune control within our cancer clients. So the key thing that you want to look about is what's causing and driving this chronic inflammation. Food is really important to assess, as we know.

So diet like standard American diet or standard British diet with its poor omega-6 to omega-3 ratio, toxic oxidized fats, high saturated fat and low fiber promoting dysbiosis, which will play into inflammation. Acrylamide from highly processed. carb foods cooked at high temperatures, high sugar and that's age-rage interactions driving inflammation, poor dietary antioxidant intake including all the phytonutrients, pesticides and additives and nutritional deficiencies and that includes vitamin D and again a number of other nutrients that we know are important for healthy immune function and immune regulation.

Sometimes if you have someone who's you're not sure about the omega-6 to omega-3 ratio then it's very quite useful to do a proper blood spot on them and have a look at their fat ratios. Dysbiosis can drive chronic inflammation, it's a factor I see play a massive role in many of my cancer clients and infections, toxins, drugs and alcohol, stress, trauma and sleep disruption are pro-inflammatory and lack of appropriate physical activity or excessive physical activity without adequate rest. So they are all factors to consider.

when we're looking at why is someone inflamed, why does someone have an elevated CRP or ESR or other markers. So interventions. Interventions particularly are split here into things we want to do from the inflammatory point of view and things that we might want to do to try and support a specific anti-tumor response.

So always start with lifestyle and inflammation. You would have heard from me a number of times, but I will reiterate it. So your anti-inflammatory whole food diet.

with correct omega-3 to omega-6 ratio, high phytonutrient index from vegetables, low sugar fruit, particularly polyphenol rich berries, herbs and spices, appropriate fasting, sleep, movement and stress management. So particularly attention in terms of herbs and spices are we know all about turmeric, we've all heard about it, particularly consumed with fat plus or minus black pepper depending on how good the gut is at that point. and how irritated the upper GI tract is because I wouldn't use it if someone has castritis for example.

Ginger, rosemary, saffron, chili, all sorts but most herbs and spices basically contain antioxidant anti-inflammatory compounds so for example parsley contains very valuable flavonoid compounds called epigenin, quercetin and luteolin. So pretty much the more the merrier and the more diversity and variety you can get the better. It's not about overdoing one thing, so just overdoing the turmeric, but actually it's all about just trying to have a balance and a mix of the different compounds. Herbal teas with anti-inflammatory and antioxidant effects, there are again plenty of them, most of them have an anti-inflammatory and antioxidant effect, but green tea, gynostemma, tulsi and ginger are particularly worthwhile mentioning. Intermittent fasting or caloric restriction is anti-inflammatory, and the latter is obviously less popular.

We do tend to opt for intermittent fasting. Don't overdo the fasting if the patient is losing weight or has a low BMI. It's not appropriate for BMI on day 18. There are different regimes, of course, we know about fasting mimicking diet, extended overnight fasts of 13 to 14 hours, 16-8 time restricted feeding or fasting days. So it just depends on your individual clinical assessment of what you think your client will be able to manage and also how metabolically dysregulated they are.

So treat the root cause always, so we're not just going to be slapping on anti-inflammatory interventions because we need to actually unplug the inflammation at its cause. So we're not going to be just mopping the floor, you need to turn off the tap. So for example, treat the dysbiosis, if there are infections driving it, if there's anything else driving this inflammation, you need to treat it, remove it or tackle it in some way.

And as I said, it's often assumed that high inflammatory markers are a consequence of cancer, but it's not always the case and you do need to look at other factors. So specific interventions we might consider, we might want to look at omega-3 and vitamin D is just the basics, you know D3 ideally would be combined with K2 unless you're on anti-oculants like warfarin for example. You would want to use antioxidants as appropriate, so always food first, don't forget that's where we should be deriving most of our antioxidants and the widest variety of phytogenes you can get. The one antioxidant I will occasionally use in combination with Active therapy, active treatments, tocotrienols, they can be very useful.

But no other high-dose antioxidant supplementation during chemotherapy until proven otherwise. And of course, other specific antioxidants that we know in specific cases are just like a prostate cancer. But again, food first still. I would normally get people to have one or two tablespoons of tomato puree with some extra virgin olive oil instead of trying to shovel a whole ton of lycopene down them. Most commonly used supplements that we use in this particular case, and again there are plenty more, this is just a small selection that have some data in cancer and that people have used clinically, but it is just a tiny bit that we can have a look at.

Curcumin, obviously we know that's one of the most popular ones for a very good reason, but caution in significantly elevated LFTs, if you do find liver function enzymes are really going off, then you will. might want to decrease your curcumin dose significantly because it can make people feel really quite a lot more nauseous. Black cumin seed and agela sativa is a rich source of thymoquinone and is a beautiful anti-inflammatory and immunomodulator. I use it a lot. Willow bark is herbal aspirin basically in the Cox inhibitor so that's a context in which we use that but much kinder on the GI lining.

Specific polyphenols is appropriate, resveratrol, EGCG, etc. There's plenty of those and some people will use CBD oil as well, which has multiple different mechanisms of action to it. So tocotrienols in cancer, so one antioxidant where actually you can combine it with certain therapies, not necessarily every single therapy, but it might be useful in some active cancer treatment. So gamma and delta tocotrienols specifically. have the highest anti-cancer activity and target a whole number of pathways.

For example, inhibiting cell cycle, induction of apoptosis and autophagy, inhibition of invasion metastasis and angiogenesis. And actually what's really interesting is that tocotrienols appear to synergize with both pharmaceutical antitumor agents such as chemotherapy, statins and some of the other targeted therapies or natural compounds again with EGCG, resveratrol, ferulic acid for example. So It's a really important tool that's very useful for us.

And it's important that we use gamma and delta tocotrienols, not just in general vitamin E. As we know, most vitamin E in supplements is not such a great quality and relies heavily on alpha-tocopherol, for example, instead of the tocotrienols, which are the truly valuable compounds. We've got to remember that tocotrienols and tocopherols often compete for absorption.

So actually it would be better to give tocotrienols alone rather than in combined formulae. There was a phase 2 trial of bevacizumab, which is an anti-VEGF drug, combined with tocotrienols in chemotherapy of refractory ovarian cancer. And what was amazing in that is the rate of disease stabilisation was 70%. So that's 70% of those patients with ovarian cancer which did not respond to chemotherapy stabilised on... Bevacizumab with tocotrienols with very low toxicity and the median progression free survival was about seven months and overall survival was about 11 months and this is late stage ovarian cancer and this is high compared to the current literature so it was significantly synergistic in this combination certainly something to consider and there are multiple studies mainly in cells and animals that showing effects on NF-kappa b synergy with the different chemotherapy agents and reversal of multi-drug resistant, as well as inhibition of the stemness, which is a stem cell property in cancer stem cells.

And a number of things that we might want to consider about when thinking about JAK-STAT pathway, which we talked about as a really key driver, you know, talking back to the beginning of the lecture where we said IL-6. kind of JAK-STAT and then you also have the other interaction with NF-kappa-B as well. So number of different compounds is a huge amount to choose from that interferes with things in different components of this JAK-STAT pathway from the top to the bottom and there are a number of them that act at specific at several different points so for example EGCG acts at the point of the top bit as well as the bottom bit in terms of the target genes. You also find that resveratrol and curcumin will act in a number of different parts of the pathway. Let's talk a little bit about polyphenols because polyphenols have significant anti-inflammatory and antioxidant actions.

And I think it's important for us to get a bit of clarity about what polyphenols actually are. So polyphenols include two different groups. They're plant-derived compounds that include two different groups of chemicals, non-flavonoids and flavonoids.

So non-flavonoids chemical compounds that exist within plants include HBA and HCA and still beans. And they're the ones we hear quite a lot about, and that's terastilbene and resveratrol in particular. Then we look at flavonoids in a number of different groups.

Flavanols, such as EGCG, that's a very popular one, of course, as we know, within cancer support. Flavanols, and that's quercetin, camphorol, and muricetin. Isoflavones as we know in terms of being soy derived, genistein, diazine, anthocyanidins and number of those around and flavonoids and that's hesperidin and noreginin and they're really quite a lot more enriched in the citrus fruit in particular.

So there are some specific antioxidant flavonoids that are useful in the context of cancer for multiple different effects but particularly things like EGCG, genistein, diazine are used quite a lot. quercetin, apigenin, christian and luteolin and many many others. The above are just the most studied and I will share a paper on the learning platform that talks you through all the various compounds and kind of where they come from and how they might be helpful and some of the evidence around those.

So I want to just highlight a few specific whole foods that as well as plant extracts that can be quite useful. To use and see ginger is anti-inflammatory, it also has anti-proliferative and anti-tumor activities and what we do know is a ginger extract in six gingerol which is one of the compounds found in ginger they actually they activate Nrf2, they decrease activation of TNF alpha, ROS and F-kappa B and COX-2 pathways and there are different options for using ginger you know always use it in food ginger decoction and I find that generally The herbs, leafy herbs in general, we think about in herbalism are better brewed as tea, but roots really need to be decocted, which means actually boiled in boiling water for a little bit of time to be able to extract all the different compounds within it. And we want to try and keep the lid on so we don't let too many of the lovely volatile chemicals escape, so sort of try and do it with a partially sharp lid when you do the decoction.

So plain tea, plain ginger tea is fine, it doesn't achieve maximal extraction so ideally you'd want to decoct your grated ginger for about 10 minutes if possible and we of course can also use it as a supplement. Not forgetting the fact that also ginger can have other effects in terms of being supportive to the gut and reducing nausea so a number of ways of using it to support our clients with cancer. Curcumin, I mean what doesn't it do really should be the question.

So, of course, within this particular talk, we are going to remind ourselves that curcumin has been demonstrated to have a significant anti-inflammatory effect through multiple different signaling pathways, including NF-kappa B, JAK-STAT, and TGF-beta pathways. And so it also activates, of course, as we know, the apoptotic pathways and inhibits inflammation, geogenesis, and metastasis. And a number of things that we'll also target that are to do with... Apoptosis is things to do with p53, RAS which is more about driving cell proliferation, PA3K and PKB which are involved in the metabolic side of things, and beta-catenin and Wnt and mTOR which are involved in both metabolic but also the stem cell pathways. The other things to say is that curcumin of course goes broader than that and also exerts beneficial effects on cancer treatment related toxicities such as kidney toxicity, cardiotoxicity and toxicity to the nervous system.

So it's a very useful multi-agent to use in a number of different settings. In terms of which curcumin, I mean, there are so many formulations in the market. At one point, I will do a review which one are the most kind of bioavailable and dosing, etc. But what we do know is that Lipocirc and Meriva have been studied in cancer specifically. And Meriva is a...

Lethizynized formulation of curcumin for better bioavailability and you can get a soy-free version as well. So just a quick reminder the fact that curcumin has been found to work alongside chemotherapies in a number of different settings including prostate cancer, liver cancer, gastric cancer, blood and colorectal. So something to keep in mind, the fact that it's a compound that has been used alongside some of the active chemotherapy drugs. And there are many, many ongoing trials with curcumin. Here's just a tiny, tiny selection, but there are a number of them and you can see they're being used in combination with chemotherapy quite a lot of the time or after significant interventions like prostatectomy.

So it's really important and even in the prevention setting there's actually a trial for nano emulsion of curcumin for obesity, inflammation, breast cancer prevention so it'd be interesting to see where that shows up. So if you are trying to use it within a specific setting just put curcumin and whatever drug of choice your client is on in PubMed and see if there been any studies on the combination because it might be useful to you to have that as a backup. Black cumin seed or Nigella sativa and inflammation cancer.

Thymoquinone is a major active constituent of black cumin seed and has a huge number of different effects. There are a number of ways in which thymoquinone mediates cancer activity. It will affect p53, NF-kB, STAT3 which we talked about as major pro-inflammatory drivers. It will also affect the nutrient metabolic sensing mechanisms and it will affect the pro-growth and pro-proliferation signaling pathways such as PI3K and ACT.

So you can see a number of different molecules are being affected here and there's also early evidence around enhancement of NK cell-mediated cytotoxicity so maybe instead of an anti-inflammatory it's actually more of an immunomodulator something like medicinal mushrooms. So talking about medicinal mushrooms, we are now moving on from just doing anti-inflammatory interventions to thinking about supporting anti-tumor response. And so specifically, we're going to talk about medicinal mushrooms PSK and two other mushroom products licensed in the Far East for supportive care during cancer treatment. There's astragalus membranaceus, which is a wonderful TCM herb that's used to support systemic immunity and ameliorate immunosuppression. It actually activates the...

T-cell tumour kill function and M1 macrophages in the tumour microenvironment. And there's some very early studies in andrographis as well. Medically, of course, they use immunotherapy, and we know that particularly with the checkpoint inhibitors, we need a healthy gut microbiome, and they do carry a risk of new onset autoimmunity, which is tricky.

Ideally, from the medical point of view, the medics would minimise steroids unless absolutely necessary because you're suppressing tumour-specific immunity anyway. And you might want to consider gastro-resistant aspirin, particularly in colorectal cancer. So that's really with regard to Cox inhibition. And there's a caution with NSAIDs.

Again, NSAIDs are quite overused within the cancer setting. And while they do have some beneficial effects, there are other ways of inhibiting the same pathways without risking GI toxicity and kidney toxicity from NSAID overuse. And of course the other interventions are out of scope for nutrition professionals but you can also refer to for mistletoe to optimize quality of life and support immune system balance and LDN is also used off-label for immunomodulation. So mistletoe therapy part of the way it works is immunomodulatory lectins and a number of different brands like Iscador, Helixor and Obnobufraxine and it must be at minimum subcutaneous and there's no proper really good data on oral even though Royal London Hospital for Integrative Medicine insists on using mostly oral but actually having done an evidence review I see very little evidence for this but much better evidence for subcutaneous injection and it's offered by a number of different integrative medicine doctors and there's a major centre in Scotland called Camp Hill Wellbeing which is well worth referring to.

It's not always appropriate straight away. It's one of those things whereby people just get thrown onto mistletoe but when you have very high inflammatory markers, when I have some of my patients who have CRPs of in excess of 150 or 200 or someone's ESI is 80, you really don't want to be waiting in there with mistletoe first. You want to try and reduce the inflammation a bit before you get mistletoe started or starting at a very very low doses. And it's not appropriate if you've got active brain mets with cerebral edema and there's room for argument for whether you can do it in other cases after treatment for the metastases. In terms of summary, just to remind you that our key goals are to decrease inflammation, oxidative stress, support immune surveillance and a balanced specific anti-tumor response.

and that's trying to get that Th1 polarisation away from the Th2 in immunosuppressive environment the tumour is trying to generate. For assessment, at minimum, get neutrophil to lymphocyte ratio, platelet to lymphocyte ratio, easy to do from full blood count, vitamin D, CRP and ferritin, and if you can get it, try and add ESI and LDH because they're useful. Look at root causes appropriate excess oxidative stress if you're looking at three to six months post active therapy and review SNPs in the wider panels just to see whether the person is more likely to exhibit an exaggerated inflammatory response.

Support of course we talked about the anti-inflammatory whole food based diet rich in phytonutrients. We do need to incorporate dietary mushrooms you'll get a new lecture on mushrooms shortly and of course the herbs and spices. Anti-inflammatory other lifestyle interventions combining nutrition with fasting, appropriate movements, supplementation, stress management, don't forget to check your interactions with your supplements, and supporting immune surveillance and anti-tumor responses for us will include things like medicinal mushrooms and astragalus. We can argue about whether nigella sativa or black cumin seed belongs in this category as well, and consider referral for other therapies if more support is needed.

Thank you very much for listening.

Transcript for:3.5 Immune Function in Cancer

Transcript for:
3.5 Immune Function in Cancer