Colonic Microbiota Promote Antitumor Immunity in Colorectal Cancer

The host microbiome can broadly affect human health, and different microbiome compositions can shape the host immune response. The colon microbiota has been associated with protumorigenic and antitumorigenic effects, underscoring the need to better understand the highly context-dependent roles of the colon microbiota in cancer. To investigate the specific contributions of the immunogenic intestinal bacterium Helicobacter hepaticus (Hhep) in colorectal cancer, Overacre-Delgoffe and colleagues colonized a murine model of colitis-associated colon cancer with Hhep, showing that Hhep colonization improved survival, reduced tumor number and size, and increased tumor-infiltrating T cells, B cells, and CD11c⁺ cells. Single-cell RNA-sequencing analysis further found that Hhep colonization increased infiltration of lymphocytes with cytotoxic functions. Notably, antibody depletion experiments demonstrated that the antitumor effects of Hhep colonization were primarily dependent on CD4⁺ T cells but not CD8⁺ T cells, and flow cytometry analysis of Hhep-specific CD4⁺ T cells revealed an increase in the proportion of T follicular helper (Tfh) cells in the colonic lamina propria. Hhep colonization also appeared to expand the colonic lymphatic network, enriching for clusters of cells expressing genes associated with stromal, endothelial, and lymphatic cells, as well as increasing expression of genes required for lymphangiogenesis, such as Pdpn and Vegfc. Immunofluorescence analysis of organized structures near colon tumors of Hhep-colonized mice provided evidence for the induction of tertiary lymphoid structures (TLS), which are defined as ectopic lymphoid formations that develop in nonlymphoid tissues in response to chronic inflammation and have been associated with a positive prognosis in colorectal cancer. These TLSs contained Hhep and Hhep-specific CD4⁺ T cells, supporting the hypothesis that Hhep-containing TLSs function as sites of activation for Hhep-specific CD4⁺ T cells. Indeed, Hhep-specific CD4⁺ T cells were sufficient to restore antitumor immunity in Tfh cell–deficient mice, and Tfh cells were necessary for Hhep-mediated tumor control. In summary, this work elucidates the mechanism by which the colon microbiota promotes antitumor immunity and highlights the therapeutic potential of microbiome-based treatment in colorectal cancer.

Overacre-Delgoffe AE, Bumgarner HJ, Cillo AR, Burr AHP, Tometich JT, Bhattacharjee A, et al. Microbiota-specific T follicular helper cells drive tertiary lymphoid structures and anti-tumor immunity against colorectal cancer. Immunity 2021;54:2812–24.e4.

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