Th166 - The Human Commensal Bacterium, Erysipelatoclostridium Ramosum, Stimulates Cytotoxic CD8 T Cells and Overcomes Resistance to Cancer Immunotherapy

Abstract Text: The gut microbiome impacts the efficacy of cancer immunotherapies in mouse models and patients. However, the mechanisms by which bacteria in the gut impact anti-tumor immunity in fighting tumors outside of the gut are unclear and microbiome-based therapies remain elusive. We have isolated a human commensal bacterium, Erysipelatoclostridium ramosum, that overcomes microbiome dependent resistance to immunotherapy. E. ramosum increases CD8 T cell proliferation in tumors and promotes anti-tumor responses in mice when orally administered live or dead. In vitro, co-culture of mouse or human CD8 T cells with dead E. ramosum, but not E. ramosum culture supernatant stimulates cytotoxic T cell proliferation and increases Granzyme B, perforin, and interferon gamma production suggesting that E. ramosum surface metabolites, and not secreted metabolites, stimulate cytotoxic T cells. To assess the specificity of E. ramosum for T cell stimulation, we tested 12 strains of human commensal bacteria in our co-culture system. While exposure to most bacteria trigger T cell death, E. ramosum can be cultured at doses up to 100 times higher than other commensal organisms and promotes cytotoxic CD8 T cells without inducing cell death. Furthermore, E. ramosum overcomes proliferation deficiencies induced by T cell proliferation inhibitors including p38, ERK, JNK, NFAT, JAK, PI3K, or AKT inhibitors. These results indicate that E.ramosum has a unique ability to stimulate CD8 T cells without damaging the immune response. Harnessing the mechanisms by which E. ramosum stimulates cytotoxic CD8 T cells could lead to more effective T cell-dependent cancer immunotherapies.