Immunotherapy efficacy in colorectal cancer is dependent on activation of a microbial-metabolite-immune circuit

Mager, L.; Burkhard, R.; Cooke, N.; Brown, K.; Ramay, H.; Paik, S.; Stagg, J.; Grooves, R.; Gallo, M.; Lewis, I.; Geuking, M.; McCoy, K.

doi:10.1101/2020.02.26.965533

bioRxiv · 10.1101/2020.02.26.965533

Immunotherapy efficacy in colorectal cancer is dependent on activation of a microbial-metabolite-immune circuit

Mager, L.·Burkhard, R.·Cooke, N.·Brown, K.·Ramay, H.·Paik, S.·Stagg, J.·Grooves, R.·Gallo, M.·Lewis, I.·Geuking, M.·McCoy, K.

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Abstract

Cancer is a leading cause of death globally. Checkpoint blockade therapies offer a promising treatment for many cancers, but have been ineffective for colorectal cancers. Previous studies have shown a dependency of immunotherapies on the microbiota. Consequently, we hypothesized that specific gut bacteria promote immunotherapy for colorectal cancer. We identify three commensal bacteria and a microbial metabolite, inosine, that enhance the efficacy of immune checkpoint blockade therapy in colorectal cancer. We show that inosine interacts with the adenosine A2A receptor on T cells resulting in intestinal Th1 cell differentiation. Decreased gut barrier function induced by immunotherapy increased the translocation of bacterial metabolites and promoted cancer protective Th1 cell activation. This microbial-metabolite-immune circuit provides a mechanism for a new class of bacteria-enhanced checkpoint blockade therapies. The efficacy of this mechanism differs among colorectal cancer subtypes and highlights the strengths as well as potential limitations of this novel bacterial co-therapy for cancer.

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Mager, L., Burkhard, R., Cooke, N., Brown, K., Ramay, H., Paik, S., Stagg, J., Grooves, R., Gallo, M., Lewis, I., Geuking, M., McCoy, K.. 2020-02-27. Immunotherapy efficacy in colorectal cancer is dependent on activation of a microbial-metabolite-immune circuit. https://doi.org/10.1101/2020.02.26.965533

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