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.
Author Info: (1) Department of Pathology. (2) Department of Pathology. (3) Department of Pathology. (4) Department of Pathology. (5) Department of Biotechnology, and. (6) Department of Patholog
Author Info: (1) Department of Pathology. (2) Department of Pathology. (3) Department of Pathology. (4) Department of Pathology. (5) Department of Biotechnology, and. (6) Department of Pathology. (7) Department of Pathology. (8) Department of Surgery, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. Surgical Oncology Unit, Rabin Medical Center, Beilinson Campus, Petach Tikva, Israel. (9) Surgical Oncology Unit, Rabin Medical Center, Beilinson Campus, Petach Tikva, Israel. (10) Surgical Oncology Unit, Rabin Medical Center, Beilinson Campus, Petach Tikva, Israel. Wolfson Medical Center, Holon, Israel. (11) Department of Pathology. (12) Department of Pathology, Stanford School of Medicine, Stanford, California, USA. (13) Department of Pathology. (14) Department of Pathology.
