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.

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.

Further evidence that the microbiome can improve melanoma cancer therapy

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