Leveraging extrafollicular B cells for the treatment of solid tumors 2260703

Abstract

Abstract Introduction Intratumoral memory B cells (MBCs) correlate with immunotherapeutic response in cancer patients. MBCs are often associated with germinal center reactions but may also be cued by the extrafollicular (EF) response, which predominates in chronic infections and autoimmunity. In autoimmunity, EF responses are driven by toll-like receptor (TLR) 7, but in the cancer setting we show TLR9 stimulation results in more functional subsets, suggesting the initial activation signal is crucial for effective B cell responses. Our lab has demonstrated that EF MBC subsets are dysfunctional in the tumor microenvironment, defined by hyporesponsiveness to BCR stimulation, impaired antibody secreting cell differentiation, and poor antibody production. We showed that EF MBCs accumulate in the peripheral blood and tumors of head and neck cancer patients, correlating with advanced stage disease. Importantly, EF populations predominately generate IgG, poising this MBC subset as an antigen specific population that may contribute to antitumor immunity through the production of tumor reactive antibodies. Thus, we hypothesize that reinvigoration of EF MBCs may contribute to tumor-specific immunity through antibody dependent cell cytotoxicity Methods This study utilizes ex vivo profiling of patients tumors and in vitro co culture systems. Results Here, we investigate discrete phenotypes of EF MBC subsets within head and neck cancer patients, finding that EF MBCs are phenotypically diverse in co-expression of integrin-adhesion molecules (CD11c, CD18), and inhibitory receptors (PD-1, FcRL5). We show that expression of FcRL5 is associated with blunted proliferation in tumor infiltrating B cells and advanced stage tumors. Blocking FcRL5 in vitro restores of proliferative capacity and increases differentiation to antibody secreting cell subsets. Conclusion Together, these data suggest that FcRL5 is a negative regulator of MBC function, highlighting a potential new axis for B-cell specific therapies in the treatment of solid tumors. Funding Source NIH F31 Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)