Antigen presentation by clonally diverse CXCR5+ B cells to CD4 and CD8 T cells is associated with durable response to immune checkpoint inhibitors.

ICI (immune checkpoint inhibitor) induced durable tumor control has been attributed to the activation of cytotoxic T cells expressing high levels of interferon gamma (IFNy) in the tumor microenvironment (TME). Interestingly, tumors of melanoma patients treated with MAPK pathway inhibitors (MAPKi) also displayed increased infiltration of cytotoxic, IFNy-secreting T cells. Yet, the rate of durable tumor control after ICI is almost twice that of MAPKi. Our analysis revealed that, while response to ICI and MAPKi both increase intratumoral T cell infiltration and interferon pathway activity, only ICI-responding tumors demonstrate increased infiltration of B cells. Specifically, in response to ICI, CXCR5+ germinal center-like B cells and CXCR5+ follicular helper T (Tfh) cells were recruited by CXCL13-producing, CD8 T cells; CXCL13 was induced in response to ICI but not MAPKi. These B cells subsequently present antigens to the CD8 T and Tfh cells through the MHC-I and -II pathways, respectively. The T cells then induce B cells' CD40L/CD40 and IFNy signaling pathways, further enhancing their antigen presentation activity. Accordingly, patients with higher levels of both BCR clonal diversity (allowing more B cell clones to present tumor antigens) and IFNy signaling activity (suggesting antigen-specific T cell activation) survived significantly longer than those with only either high BCR clonal diversity or IFNy pathway score. Thus, ICI, but not MAPKi therapy, induces the recruitment of clonally diverse antigen presenting B cells that activate antigen specific Tfh and cytotoxic CD8 T cells to effect a durable antitumor immune response. ### Competing Interest Statement The authors have declared no competing interest.