Neoantigen-driven B cell and CD4 T follicular helper cell collaboration promotes anti-tumor CD8 T cell responses

CD4 T follicular helper (TFH) cells support B cells, which are critical for germinal center (GC) formation, but the importance of TFH-B cell interactions in cancer is unclear. We found enrichment of TFH cell transcriptional signature correlates with GC B cell signature and with prolonged survival in individuals with lung adenocarcinoma (LUAD). We further developed a murine LUAD model in which tumor cells express B cell- and T cell-recognized neoantigens. Interactions between tumor-specific TFH and GC B cells, as well as interleukin (IL)-21 primarily produced by TFH cells, are necessary for tumor control and effector CD8 T cell function. Development of TFH cells requires B cells and B cell-recognized neoantigens. Thus, tumor neoantigens can regulate the fate of tumor-specific CD4 T cells by facilitating their interactions with tumor-specific B cells, which in turn promote anti-tumor immunity by enhancing CD8 T cell effector functions. [Display omitted] •Enrichment of TFH and GC B cells correlates with favorable clinical outcomes of LUAD•B cell-recognized neoantigens drive tumor-specific B cell and TFH cell responses•Tumor-specific TFH cells produce IL-21•IL-21 is critical for tumor control and tumor-infiltrating CD8 T cell effector function B cells promote the differentiation of tumor-specific CD4 T follicular helper cells in a neoantigen-dependent manner, which in turn enhance CD8 T cell effector functions by producing IL-21 and drive anti-tumor immunity in a murine model of lung adenocarcinoma.