Bifidobacterium catenulatum boosts anti-PD-1 efficacy in microsatellite stable colorectal cancer via activating CD8 + T cells

Background Certain gut bacteria are associated with improved responses to immunotherapy. Objective We aim to identify bacteria that inhibit colorectal cancer (CRC) progression and enhance immunotherapy efficacy. Design The abundance of bacteria in CRC patients was evaluated in our in-house cohorts and validated in published datasets. The effect of candidate bacterium with anti-PD-1 therapy was determined in two syngeneic mouse models of MC38 (microsatellite instability-high) and CT26 (microsatellite stable, MSS), transgenic Apc min/+ mice and azoxymethane/dextran sulfate sodium (AOM/DSS)-induced CRC tumourigenesis model. Immune landscape changes were identified by multicolour flow cytometry and immunohistochemistry staining. Metabolomic profiling was performed on stool, serum and tumour tissues. Results Bifidobacterium catenulatum was significantly depleted in stool samples of 110 CRC patients compared with 112 healthy controls, which was further validated in 3 published metagenomic datasets comprising 198 CRC patients and 176 normal subjects. Oral administration of B. catenulatum inhibited tumour growths in multiple CRC models including MC38 and CT26 syngeneic models, Apc min/+ mice and AOM/DSS-induced CRC. Notably, B. catenulatum synergised with anti-PD-1 therapy through enhancing intratumoural CD8 + T cell infiltration in MSS CRC models of Apc min/+ mice and CT26 allografts. B. catenulatum- derived acetate was identified as the functional metabolite. Mechanistically, acetate directly bound to MCT-4 in CD8 + T cells and activated mitogen-activated protein kinase signalling. Pharmacological and genetic MCT4 ablation abolished acetate-mediated CD8 + T cell activation in vitro. Conclusion B. catenulatum suppresses colorectal tumourigenesis through generating acetate, which also improves anti-PD-1 efficacy through activating CD8 + T cells in MSS CRC. B. catenulatum is a potential adjuvant to improve immunotherapy against CRC.