Microbiota-Specific T Follicular Helper Cells Drive Anti-Tumor Immunity in Colorectal Cancer 9339

Abstract Description Colorectal cancer (CRC) remains one of the leading causes of cancer mortality worldwide, and the efficacy of immunotherapy for CRC has been limited. Emerging evidence suggests that the gut microbiota can profoundly influence immune responses to tumors. Here, we demonstrate that colonization with Helicobacter hepaticus (Hhep) in CRC-bearing mice induces microbiota-specific T follicular helper cells (TFH), which are essential for anti-tumor immunity. Hhep-specific TFH cells drive the formation of tertiary lymphoid structures (TLS) near tumors, facilitating local immune responses. TLS development was correlated with reduced tumor burden and enhanced survival in these models. We further explored the mechanisms underlying these effects by colonizing CRC-bearing mice with different Helicobacter species, including H. hepaticus, H. bilis, and H. pullorum. Our results revealed that while H. hepaticus and H. bilis strongly induce TFH and TLS formation, H. pullorum does not. Additionally, using IgMi mice, we observed that both homozygous and heterozygous IgMi mice developed comparably severe tumors, suggesting a critical role for the gut microbiota and immune mechanisms beyond antibody production in regulating tumor progression. This study uncovers the critical role of microbiota-specific TFH cells and TLS in orchestrating anti-tumor immunity in CRC and provides insights into leveraging microbiota-immune interactions to develop novel therapeutic strategies for CRC immunotherapy. Funding Sources Supported by NIH CA269902 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)