Rasoulouniriana et al. show that murine syngeneic solid tumors regressed upon transfer of tumor antigen-specific antibodies and CD4+ T cells isolated from tumors and draining lymph nodes but not blood. Non-proliferating, exhausted CD4+ T cells expressed high-affinity IgG Fc receptor (FcγRI) and lysed antibody-coated MHC II+ tumor cells in vitro via IFNγ-dependent granule secretion. Conventional murine CD4+ T cells transduced with tumor antigen-specific TCRs and with signaling-competent FcγRI synergized with tumor-specific antibodies to induce lysis in vitro and tumor regression. FcγR+ CD4+ T cells were also identified in human tumor samples.
Contributed by Paula Hochman
While a high frequency of Th1 cells in tumors is associated with improved cancer prognosis, this benefit has been attributed mainly to support of cytotoxic activity of CD8+ T cells. By attempting to potentiate antibody-driven immunity, we found a remarkable synergy between CD4+ T cells and tumor-binding antibodies. This surprising synergy was mediated by a small subset of tumor-infiltrating CD4+ T cells that express the high-affinity Fcgamma receptor for IgG (FcgammaRI) in both mouse and human patients. These cells efficiently lyse tumor cells coated with antibodies through concomitant crosslinking of their T cell receptor (TCR) and FcgammaRI. By expressing FcgammaRI and its signaling chain in conventional CD4+ T cells, we successfully employed this mechanism to treat established solid cancers. Overall, this discovery sheds new light on the biology of this T cell subset, their function during tumor immunity, and the means to utilize their unique killing signals in immunotherapy.