Further evidence that the microbiome can improve melanoma cancer therapy

T stages of melanoma

Yesterday we discussed a paper that discussed how the microbiome impacted a melanoma cancer therapy.  In the same issue of Science another article was published where researchers from Chicago independently made a similar discovery - that the microbiome itself can impart an anti-tumor effect on melanoma.

The scientists were using a  common mouse model for melanoma between two different laboratories (Taconic Labs and Jackson Labs) when they noted that the cancer progressed much differently between the labs.  The Taconic mice had more aggressive cancer than the Jackson mice.  They hypothesized that one possible difference between the mice in the two labs were their microbiomes.  In fact, when the Taconic mice were given the Jackson mice's microbiomes, the Taconic mice's cancer grew more slowly.  The scientists then attempted to identify which bacteria were having the effect.  They compared the mice's microbiomes and discovered that Bifidobacteria were much more abundant in the Jackson mice.  Upon treating the Taconic mice with strains of Bifidobacterium longum and Bifidobacterium breve the Taconic mice's cancer grew more slowly.  Interestingly, the scientists discovered that the bacteria were likely increasing the activation of T-cells, because mice that had mutated T-cells did not have the microbiome-mediated anti-cancer effect.

This study points to an exciting role of the microbiome in mediating and activating the immune system to attack and destroy some cancers.  The researchers note that there are likely other microbiome bacteria that have this effect, but that they have only identified the Bifidobacteria.  Hopefully the scientists will be able to measure the effect in humans, and observe an association between patient outcome and the presence and absence of certain gut bacteria.

Melanoma cancer therapy’s efficacy may depend on the existence of specific gut bacteria

Ipilimumab is a monoclonal antibody (mAb) that binds to, and activates T-cells. (Technically, the drug binds to the CTLA-4 receptor on T-cells, which decreases T-cell suppression)  It is currently an approved therapy for the treatment of metastatic melanoma.  Unfortunately, activation of the immune system can damage the microbiome, and taking iplimumab often results in adverse side effects in the gut, such as diarrhea.  Scientists from France were studying the effect of the drug on the microbiome when they discovered that its efficacy was actually dependent on the presence of certain gut bacteria.  They published their results in the journal Science.

First, the scientists administered the ipilimumab to three groups of mice that had been given cancer through an established model.  One group of mice had a normal microbiome, the second group was germ-free, and the final group had a normal microbiome, but then were given antibiotics.  Surprisingly, the mAb activated much fewer T-cells and was much less effective in destroying the cancer in the mice that were germ free and had been given antibiotics compared to the normal mice.  In addition, the scientists noted that intestinal inflammation occurred in the normal mice, but less so in the others.  Next, the scientists measured the microbiome changes as a result of administration of the mAb, and observed a rapid decrease in Bacteroidales, Burkholderiales, and an increase in Clostridiales.  The scientists then inoculated cancerous mice with specific bacterial species prior to administration of the drug, and then measured the drug’s efficacy.  Remarkably, specific species, such as Bacteroides thetaiotaomicron were able to reestablish the drug’s therapeutic potential and decrease inflammation.

The microbiome’s complex dynamic with the immune system once again presents itself, this time by modulating the efficacy of ipilimumab.  The scientists did do some work on humans, and they noted that not all human patients suffering from melanoma and taking ipilimumab have those beneficial bacteria in their stool.  The scientists did not discuss whether their existence was associated with the cancer’s progression in humans, although it would be interesting to see.  Ipilimumab is just one of many drugs that use the immune system to attack cancer.  Continued research is needed on the microbiome’s impact on these drugs.

Antibiotic exposure may increase risk of cancer

The microbiome has been implicated in several cancers including gastrointestinal and breast cancer with many hypotheses proposed as to why bacterial dysbiosis is associated with cancer onset. Recent studies in mice as well as epidemiological studies have provided further evidence that specific bacterial composition led to tumor formation and this could be blocked by antibiotics. In a new study, scientists at the University of Pennsylvania aimed to use epidemiological data to evaluate the association between antibiotics and cancer risk of the skin, lung, breast, gastrointestinal and genitourinary tract. 

The scientists used data from The Health Improvement Network (THIN) database, a medical record database from the United Kingdom containing the information of approximately 11 million individuals. They looked at 15 different malignancies and in order to focus on sporadic cancers, they excluded any individuals with family cancer syndromes as well as any subjects that were diagnosed prior to the age of 20. With every case of cancer, they used four matched controls resulting in 125, 441 cases and 490, 510 controls analyzed for the study.

They found that the use of penicillin resulted in an increased risk of esophageal, gastric, and pancreatic cancers and was 1.4 for gastric cancers associated with greater than 5 courses of antibiotics. Lung cancer risk also increased with penicillin, cephalosporins, or macrolides. Prostate cancer also so a slight increase with several types of antibiotics as well as breast cancer after sulphonamide exposure.

They found for any type of malignancy there was no association between a single course of antibiotic use and increased risk but there was a correlation between greater number of antibiotic courses and cancer risk. Penicillin was associated with the most significant cancer risk while anti-virals, anti-fungals, and tetracylines were not associated with increased risk of cancer. While the increase in incidence was quite small (approximately 20:100,000), it is an important finding that antibiotics may be having a wider impact than previously believe. It is important that future studies look at the mechanisms for how antibiotics are causing this increased cancer risk as well as the effects of age of antibiotic exposure on cancer risk.

Americans swap foods with Africans and their microbiomes follow – fiber, fat and cancer risk

Phuto pap and porridge, a traditional South African, high fiber, meal.

Despite having similar genetic backgrounds, African Americans are thirteen times more likely to develop colon cancer than rural South Africans.  Indeed, environmental factors, rather than genetics, are thought to be the major factor in developing colon cancer, because recent immigrants’ children’s risk is more similar to where they are living than to their parents’ homeland.  This environmental risk could be primarily caused by a number of factors, such as antibiotic use or drug use, but many scientists believe that diet, and its influence on the microbiome, is primarily responsible.  As it turns out, rural Africans eat much more fiber (almost 5x more) and much less fat (almost 3x less) than African Americans, and these differences have drastic effects on the microbiomes of their hosts.  Not only are the most abundant bacterial species different, but the major metabolites vary greatly as well.  Scientists from the University of Pittsburgh came up with the clever idea of swapping the foods of rural South Africans and African Americans, to investigate how this dietary intervention would affect each group’s microbiomes and risk for colon cancer.  They published the results of their study in Nature Communications last week.

The researchers studied 20 middle aged African American men and 20 middle aged rural South African men.  They each had their microbiomes and colons studied for two weeks while eating their normal diets, and then again for two weeks after swapping diets.  Initially, the Americans had microbiomes dominated by Bacteroides and the Africans by Prevotella.  After the diet though, they noticed a rapid shift in these populations, and it corresponded to an increase in colonic inflammation for the Africans and decrease in the Americans.  In addition, an increase in butyrate, the short chained fatty acid (SCFA) that is thought to be beneficial to health, followed the fiber diet as well, and a decrease was associated with eating the high fat diet; this makes sense, as butyrate is produced as a metabolite of fiber fermentation by the microbiome.  Interestingly, prior to the diet change a top-level analysis of all the metabolic end products of the microbiome showed that Africans produced more of every single one studied except for choline, which is related to heart disease.  Many of the metabolites studied, including choline, followed their diet switch, and were produced according to the food eaten, rather than the person eating it.  Perhaps most importantly, secondary bile acids, which are produced by the microbiome and may be carcinogenic and an important cause of colon cancer, followed the diet as well.  Africans, who produced much fewer secondary bile acids than Americans while consuming their regular diet, had a 400% increase in production after the diet switch, and vice versa for the Americans, who had a 70% decrease.

This study really illustrates the importance of diet on the output of the microbiome.  These metabolites can directly influence our health, and may be more important to our well-being than the bacteria that produce them.  According to this study, it appears that eating more veggies and less fat, something that parents have been saying for a long time, fits in with our understanding of the microbiome.  As Erica Sonnenburg said in our podcast 3 weeks ago, “Feed your microbiome at every meal!”

Major advance in possible bacterial treatment for cancers

Salmonella bacteria

Editor’s note: Yesterday we wrote about how microbiome bacteria may be protecting cancer cells, but today we wanted to write about how microbiome bacteria can be engineered to kill cancer cells.  Enjoy.

In 2003 a group at the Harvard Medical School discovered that nonpathogenic Salmonella (a microbiome bacterium) that was injected into mice would preferentially accumulate in the tumors of those mice, sometimes by a factor of 10,000.  Soon after, the researchers tried to apply these findings to target and destroy cancer cells.  They began incorporating cancer-fighting proteins into the Salmonella with the hopes that the bacteria would accumulate in tumors and destroy them.  This was effective in killing the cancer, but the Salmonella was not specific enough to tumors, and the low levels that existed in healthy tissues still expressed anticancer proteins which killed the healthy tissues.  Recently though, this problem may have been solved.  One of the original scientists from Harvard Med, who now has his own group at UMass Amherst, developed a clever way to only trigger the anticancer proteins in Salmonella that are on cancer cells.  His group published their results in the Proceedings of the National Academy of Sciences on Wednesday.

The scientists incorporated a genetic switch in the Salmonella which would only trigger the production of anticancer proteins around cancer cells.  In order to do this they took advantage of the fact that the Salmonella accumulates to higher concentrations on cancer cells.  Many bacteria have proteins called quorum sensing proteins.  They are used by individuals and communities to sense what is around them, and to communicate with other bacteria.  Some of these quorum sensing proteins are only activated by their genes when there are enough other bacteria around them.  The scientists from UMass utilized this fact to incorporate a quorum sensing gene into Salmonella that would only activate a specific protein when it was around a high concentration of other Salmonella (e.g. in cancer cells). 

The scientists incorporated this quorum sensing gene into Salmonella so that, when triggered, it would express a fluorescent protein (which could be easily visualized).  They then injected these Salmonella into mice with various tumors.  They discovered, as they had hoped, that the fluorescing protein was predominantly expressed in cancer cells, and at very low levels elsewhere.  Moreover, the fluorescent protein was expressed for at least 24 days, and it did not appear to be expressed in other tissues (such as the liver) at all.

These experiments provide a partial proof of concept for a unique bacterial treatment to cancer.  The next step is to test anticancer proteins instead of fluorescing proteins, but the results using the fluorescing proteins are promising.  The scientists mentioned that the Salmonella used is non-pathogenic and can be eliminated from the body through natural processes.  This is a rather innovative potential cancer treatment, and we are excited to see what its future holds.

Microbiome bacteria help cancer cells evade the immune system

Optical microscope image of bacteria from the genus Fusobacteria.

A few weeks ago Kris Campbell wrote about the microbiome’s association with colorectal cancer.  This association is complex, but perhaps critically important, and last week a new study reinforced this connection.  Researchers, primarily from Israel, published results in Cell Immunity that showed common microbiome bacteria are protecting cancer cells by helping the cancer cells evade the immune system.

The researchers noticed that a type of bacteria, Fusobacterium nucleatum, which is normally found in the oral microbiome and is a cause of periodontal disease, can be found in high concentrations around colorectal tumors.  In addition, these same bacteria had been linked to various microbiome associated diseases, such as preterm birth and rheumatoid arthritis.  They suspected that these bacteria may somehow be protecting the cancer cells from the immune system, so they performed a series of experiments to find out.

The scientists grew cancer cells in the presence and absence of the F. nucleatum and then exposed these cancers to immune system cells that are designed to attack cancers.  They noticed that those cancer cells that had been grown with the bacteria were naturally protected from these immune cells.  Through a series of tests they discovered that the bacteria produce a protein called Fap2 that naturally bound with the immune cells and essentially deactivated them (technically speaking, Fap2 bound to the Natural Killer cells’ TIGIT inhibitory receptors).  Interestingly, this TIGIT receptor is nearly ubiquitous across many types of immune system cells, which means that this bacteria, and others like it, may be especially good at protecting themselves and other cancer cells from our bodies’ natural defenses.

It may be surprising for our readers to hear that bacteria are sometimes used to destroy cancer cells, like in the case of bladder cancer, but this paper shows a more dichotomous relationship between the microbiome and cancer.  While some bacteria may be helpful in killing cancers others may be helping them grow.  Either way, one thing is clear, the microbiome and cancers are intimately related, and learning about the microbiome should lead to advanced therapies for treating cancers.