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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Categories: 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 3

A small subset of tumor-infiltrating CD4+ T cells expresses Fcγ receptors.

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A small subset of tumor-infiltrating CD4+ T cells expresses Fcγ receptor...
(A) Gating strategy and representative FACS analyses of the tumor, DLN, and blood from day-10 tumor-bearing mice. (B) Mean percentages of Fcγ receptors expressing CD4+ T cells in various organs in day-10 B16 tumor–bearing mice (n = 4). Statistical significance was calculated using 2-way ANOVA with post hoc Tukey’s test. (C) Confocal microscopy of day-10 B16F10 tumor. Original magnification, ×800. (D) Representative FACS analysis of Fcγ receptors on 4T1 tumor-infiltrating CD4+ T cells. (E) Mean percentages of Fcγ receptors expressing CD4+ T cells in various organs in day-12 4T1 tumor-bearing mice (n = 4). Statistical significance was calculated using 2-way ANOVA with post hoc Bonferroni’s test. nDLN, nondraining lymph node. (F) Confocal microscopy of day-12 4T1 tumor sections. Original magnification, ×800. Data represent mean ± SEM, and results are from 1 representative experiment out of at least 3 performed. *P < 0.05; **P < 0.01; ****P < 0.0001. P < 0.05 was considered significant.