Wennhold et al. isolated murine antigen-specific B cells, enhanced their antigen presentation capabilities with CD40 stimulation, and showed T cell stimulating properties in vitro and in vivo equivalent to dendritic cells (DC). Combining these DC-like B cells with antigen-specific B cells expressing antibody (following stimulation with CD40, IL-21, and IL-4) significantly enhanced therapeutic efficacy in a pancreatic tumor model. Similar DC-like B cells were isolated from draining lymph nodes or TILs in human cancers.
Cancer immunotherapy by therapeutic activation of T cells has demonstrated clinical potential. Approaches include checkpoint inhibitors and chimeric antigen receptor T cells. Here, we report the development of an alternative strategy for cellular immunotherapy that combines induction of a tumor-directed T-cell response and antibody secretion without the need for genetic engineering. CD40 ligand stimulation of murine tumor antigen-specific B cells, isolated by antigen-biotin tetramers, resulted in the development of an antigen-presenting phenotype and the induction of a tumor antigen-specific T-cell response. Differentiation of antigen-specific B cells into antibody-secreting plasma cells was achieved by stimulation with interleukin 21 (IL-21), interleukin 4 (IL-4), anti-CD40, and the specific antigen. Combined treatment of tumor-bearing mice with antigen-specific CD40-activated B cells and antigen-specific plasma cells induced a therapeutic antitumor immune response resulting in remission of established tumors. Human CEA or NY-ESO-1-specific B cells were detected in tumor-draining lymph nodes and were able to induce antigen-specific T-cell responses in vitro indicating that this approach could be translated into clinical applications. Our results describe a technique for the exploitation of B cell-effector functions and provide the rationale for their use in combinatorial cancer immunotherapy.