Microbiome-specific T follicular helper cells drive tertiary lymphoid structures and anti-tumor immunity against colorectal cancer

Colorectal cancer (CRC) is a common and deadly disease, and patients with metastatic tumors often fail to respond to therapy. While select members of the microbiome are associated with improved anti-tumor immunity, mechanistic understanding of how the microbiome provides a benefit is lacking. We show that modification of the CRC-associated microbiome with a single immunogenic commensal bacteria can alter T cell differentiation, inhibit tumor growth, and increase survival. Microbiome-driven control of CRC required the formation of colonic tertiary lymphoid structures (TLS) and increased infiltration of the tumor with cytotoxic immune cells. In the context of CRC, CD4+ T cells specific to the newly introduced commensals differentiated into T follicular helper cells and were necessary for the formation of TLS, immune infiltration of the tumor, and control over CRC. Thus, modification of the intestinal T cell response by the microbiome can be used to augment anti-tumor immunity in colorectal cancer. ### Competing Interest Statement DAAV: cofounder and stockholder of Novasenta and Tizona; stock holder of Oncorus and Werewolf; patents licensed and royalties with Astellas, BMS; scientific advisory board member of Tizona, Werewolf and F-Star; consultant for Astellas, BMS, Almirall; research funding through BMS, Astellas and Novasenta.