Effector CD4+ T cells, rather than CD8+, increase the efficacy of antibody-driven tumor immunity

Most studies and therapeutic strategies in tumor immunology have focused on CD8+ T cells and their cytotoxic activity, with relatively little emphasis has been placed on understanding and harnessing the CD4+ T cell response. In a recent study, aimed to dissect the changes in T cell compartment across the body of tumor-bearing mice following antibody-mediated immunotherapy, we found that antigen-experienced CD4+ and CD8+ T cells are highly associated with tumor regression. Here, we further tested which cell subset better potentiate antibody-mediated tumor immunity. Initially, we isolated effector CD8+ and CD4+ T cells from tumor-bearing mice, expend them ex vivo and inject them intravenously to mice bearing established melanoma tumors along with tumor-binding antibodies. We found that adoptive transfer of effector CD4+ T cell induced a longer, more potent tumor-protecting immunity compared to transfer of effector CD8+ T cells. Deep sequence analysis of CD4+ T cell receptors (TCR) in tumor-bearing mice revealed that T cell in different organs, and especially in tumors, have different TCR. Therefore, we sought to elucidate which organ contains the most effective tumor-reactive CD4+ T cells. To this end, we isolated effector CD4+ T cells from various organs of tumor-bearing mice, expend them ex vivo and adoptively transferred them to mice bearing large and established melanoma. We found that CD4+ T cells from tumors and draining lymph nodes, but not from blood or non-draining lymph nodes, induce regression of large established tumors. Overall, this study highlights the therapeutic capacities of CD4+ T cells and their synergism with antibody-driven immunotherapies, and provides a rationale for deeper studies aimed at leveraging CD4+ T cell responses.