Gut microbiota may be the reason why cancer immunotherapy works for some but not all
Scientists found 11 bacterial strains and a link to a cellular process in mice that influences whether their immune system fights melanoma.
This link is important because the presence of these bacteria strains and reduced UPR could point out who checkpoint blockade immunotherapy, one type of cancer immunotherapy, works for. Currently, this therapy only works for half of the patients it’s given to, sometimes stops working after some time, or comes with autoimmune-sickness like side effects. Therefore, it would be helpful to know in advance who would be helped by checkpoint blockade immunotherapy, and who wouldn’t.
We spoke with Ze’ev Ronai at Sanford Burnham Prebys Medical Discovery Institute about the group’s findings as the latest in the hunt for biomarkers in cancer immunotherapy.
ResearchGate: How do immune checkpoint inhibitors work and who do they work for?
Ze’ev Ronai: Immune checkpoint inhibitors “release the breaks” which usually protect tumors from being attacked by the immune system’.
RG: How did you come up with the idea to study the gut microbiome’s influence on cancer immunotherapy?
Ronai: An unexpected observation we made led us to explore the possible role of the gut microbiota in the control of anti-tumor immune response. We noticed that our mice, a genetically modified strain lacking one gene, were able to inhibit melanoma growth. We were surprised to find out that such inhibition was lost when the mice were treated with a cocktail of antibiotics: This implied a possible effect of the gut microbiota which is known to be deregulated following antibiotic treatment. Then we let these mice live together with non-genetically modified mice that didn’t reject the tumor. This co-housing resulted in loss of the tumor rejection phenotype, seen in the mutant mice. Since co-housing is known to affect the microbiota composition, we set to directly assess the possibility that the gut microbiota have a direct role in the activation of the immune system to attack tumors.
RG: How did you study their influence on the gut microbiome?
Ronai: We used a number of computational tools to help us dissect the information gathered from the analysis of the gut microbiota composition of our mice, comparing those that reject tumors to those that do not. This computational approach enabled us to identify a set of 49 bacterial families that were enriched in the mutant mice – which exhibit tumor growth inhibition. Further computational work allowed us to focus on 11 bacterial strains that were then directly tested for their effect on anti-tumor immunity in mice. We grew these select bacterial strains in culture and administered them to mice that lack bacteria in their gut (germ free mice), assessing the impact of these bacterial population.
RG: What did you find?
Ronai: We found that administering these 11 bacterial strains to germ free mice was effective in inducing anti-tumor immune response which limited melanoma growth.
RG: Is there anything special about these 11 bacterial strains? Are they commonly found in our gut?
Ronai: These are commonly found in the gut, some of them were shown to have a positive impact on the immune system and help activating it in context of fighting cancer, others were novel.
RG: What’s next in your research?
Ronai: Mapping the microbiota by-products – metabolites – that could have influence on the anti-tumor immunity – allowing us to cross the barrier from mouse to men.
Feature image: J.M. Richardson