Memory B cell Responses Ignite Anti-Tumor Immunity by Activating CD8+ T cell Cytotoxicity

Immunotherapies aimed at leveraging T cell responses have revolutionized cancer care with demonstrated effectiveness in a myriad of cancers. Yet, challenges remain in patients with solid tumors such as triple negative breast cancer (TNBC) that fail to generate and sustain a durable anti-tumor T cell mediated immune response. Numerous reports demonstrate opportunities to improve upon these treatments by leveraging B cells. Tumor infiltrating B cells have been shown to predict responses to chemo and immunotherapies across cancers. B cells within the tumor have also been experimentally shown to be intimately involved in controlling anti-tumor immune responses and markers for their interactions with T cells have immense prognostic value. However, experimental demonstration of how B cell responses to tumors are regulated and function remains a key gap in research, which limits leveraging B cells in future immunotherapies. Thus, we sought to understand the role of tumor antigen and activation signals of B cell-driven anti-tumor immunity. Our study has revealed that activating the CD40 pathway of B cells in the presence of neo-antigen can directly incite a robust non-germinal center (GC) memory B cell response that is able to facilitate powerful anti-tumor immune responses in mouse models of TNBC. Leveraging single cell sequencing in combination with microscopy approaches we have found that these memory B cells can participate in an anti-tumor response by promoting CD8+ T cell infiltration, organization, and stimulation of CD8+ T cells to promote tumor cell killing. These findings advance the canonical models of B cell and CD8+ T cell regulation along with function. Furthermore, these results showcases novel routes to leverage B cells to promote anti-tumor immunity.