A distinct subset of FcγRI-expressing Th1 cells exert antibody-mediated cytotoxic activity
Diana Rasoulouniriana, … , Peleg Rider, Yaron Carmi
Diana Rasoulouniriana, … , Peleg Rider, Yaron Carmi
Published October 1, 2019; First published August 26, 2019
Citation Information: J Clin Invest. 2019;129(10):4151-4164. https://doi.org/10.1172/JCI127590.
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Research Article Immunology Therapeutics

A distinct subset of FcγRI-expressing Th1 cells exert antibody-mediated cytotoxic activity

Abstract

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 Fcγ receptor for IgG (FcγRI) 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 FcγRI. By expressing FcγRI 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.

Authors

Diana Rasoulouniriana, Nadine Santana-Magal, Amit Gutwillig, Leen Farhat-Younis, Yariv Wine, Corey Saperia, Lior Tal, Haim Gutman, Alexander Tsivian, Ronen Brenner, Eiman Abu Bandora, Nathan E. Reticker-Flynn, Peleg Rider, Yaron Carmi

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Figure 6

Ectopic expression of FcγRI in canonical T cells endows cytotoxic activity and can be employed to eradicate solid tumors.

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Ectopic expression of FcγRI in canonical T cells endows cytotoxic activi...
(A) Mean percentages of membrane-bound CD107a in infected splenic CD4+ T cells cultured for 48 hours with B16 tumor cells. (B) Mean percentages of apoptotic B16 cells as indicated by annexin V/PI staining following 48 hours incubation with infected CD4+ T cells (n = 3). (C) Mean percentages of apoptotic B16 cells as indicated by annexin V/PI staining following 48 hours incubation with CD4+ T cells cultured for 48 hours with B16 tumor cells. (D) B16F10 tumor size (mm2) following adoptive transfer of transduced CD4+ T cells (n = 4). (E) Photomicrographs of tumor-bearing mice 12 days after adoptive transfer of infected CD4+ T cells. (F) B16F10 tumor size (mm2) in chimeric mice bearing BM from control (red lines) or from FcɛRIγ KO mice (blue lines) following adoptive transfer of transduced CD4+ T cells (n = 4). Data represent mean ± SD, and results are from 1 representative experiment out of at least 3 performed. Statistical significance was calculated using 2-way ANOVA with post hoc Šidák’s multiple comparisons test for A, B, and C, and Tukey’s comparisons test for D and F. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. P < 0.05 was considered significant.