Context is everything: Microbiota-specific T follicular helper cells in colorectal cancer

Colorectal cancer (CRC) is the third most common and one of the deadliest cancers in the US, and the survival rate for advanced cases is poor. Immunotherapy, especially checkpoint blockade, has revolutionized the way cancer is treated and has resulted in longterm, durable responses for some epithelial cancers. Unfortunately, CRC remains largely unresponsive to current immunotherapies, with only ~6% of total patients responding to anti-PD1. Therefore, it is necessary to not only determine hurdles that are preventing checkpoint blockade response, but to also develop novel therapies to use in conjunction with current therapies. The microbiome has recently been associated with better anti-PD1 response in melanoma patients; however, the underlying mechanism by which select bacteria provide a benefit and whether this can be applied to other cancer types remains unclear. The majority of microbes live within the gut, and adherent bacteria can have direct interaction with the colonic epithelium, resulting in a bacteria-specific immune response. Therefore, we hypothesized that rational modification of the microbiome may support anti-tumor immunity through activation of microbiota-specific T cells. Using a carcinogen-induced mouse model of CRC, we found that addition of a single colonic-residing, adherent bacteria (Helicobacter hepaticus, Hhep) after tumors had formed led to a significant reduction in tumor burden and a 2-3 fold increase in overall survival. Interestingly, Hhep colonization led to the activation of Hhep-specific T follicular helper cells (TFHs) that supported formation of large, organized tertiary lymphoid structures (TLS) found adjacent to or within tumors themselves. The presence of TLS supported an increase in cytotoxic lymphocytes (T and NK cells) specifically within the tumor core. Somewhat strikingly, the anti-tumor response was dependent on CD4⁺ T cells but not CD8⁺ T cells. Using TFH KO mice, we found that Hhep-specific T cells were both necessary and sufficient to drive TLS maturation, anti-tumor immunity, and ultimately, longterm survival in CRC. Overall, these findings suggest that microbiome modulation and the subsequent microbiota-specific CD4⁺ T cell response may represent a new immunotherapeutic target for cancer subtypes that remain resistant to checkpoint blockade. Citation Format: Abigail E. Overacre-Delgoffe, Hannah J. Bumgarner, Anthony R. Cillo, Ansen H. P. Burr, Justin T. Tometich, Amrita Bhattacharjee, Tullia C. Bruno, Dario A. A. Vignali, Timothy W. Hand. Context is everything: Microbiota-specific T follicular helper cells in colorectal cancer [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr PR08.