Overcoming microbiome-dependent resistance to cancer immunotherapy 2210

Abstract Description The gut microbiota is a crucial regulator of anti-tumor immunity during immune checkpoint inhibitor therapy. Fecal transplantation can improve the efficacy of anti-PD-1 therapy in patients with melanoma. However, the increased efficacy from fecal transplants is variable, and the mechanisms by which gut bacteria promote anti-tumor immunity remain unclear. Here, we show that the gut microbiome and specific gut bacteria downregulate PD-L2 expression on dendritic cells and its binding partner, repulsive guidance molecule B (RGMb), to promote anti-tumor immunity. Moreover, antibody-mediated blockade of the PD-L2–RGMb pathway or conditional deletion of RGMb in T cells, combined with anti-PD-1 or anti-PD-L1 antibodies, promotes anti-tumor responses in multiple mouse tumor models that do not respond to anti-PD-1 or anti-PD-L1 alone in germ-free, antibiotic-treated mice and in mice with non-responder patient microbiota. We further isolated the bacterial molecules that downregulate PD-L2 and promote anti-tumor immunity. Mechanistically, the bacterial molecules suppress PD-L2 expression in a TLR4/MyD88-dependent manner. These studies identify the downregulation of the PD-L2–RGMb pathway as a specific mechanism by which the gut microbiota can promote responses to PD-1 checkpoint blockade. The results also define a potentially effective immunological strategy for treating patients who do not respond to PD-1 cancer immunotherapy. Funding Sources Quark Ventures (A31696), National Institutes of Health/National Cancer Institute (F32-CA247072) Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)