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 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 2

CD4+ T cells from the tumor and DLN directly kill tumor cells coated with IgG.

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CD4+ T cells from the tumor and DLN directly kill tumor cells coated wit...
(A) Illustration of experimental outline. (B) B16F10 tumor size (mm2) in mice following injection of CD4+ T cells from day 7 tumor-bearing mice with anti-TRP1 and DC stimuli (n = 3). (C) Representative photomicrographs of tumor-bearing mice 7 days after adoptive transfer of CD4+ T cells. (D) B16F10 tumor size (mm2) in RAG-deficient mice following adoptive transfer of CD4+ T cells, with or without antibodies against TRP1 and DC stimuli (n = 4). (E) Confocal images of wasabi-labeled B16 tumor cells cocultured for 48 hours with CD4+ T cells obtained from day 7 tumor-bearing mice. Original magnification, ×800. (F) Percentages of dead tumor cells after 48 hours incubation with CD4+ T cells measured by flow cytometry analysis of annexin V/PI staining (n = 3). Data represent mean ± SEM, and the results are from 1 representative experiment out of at least 3 performed. Statistical significance was calculated using 2-way ANOVA with post hoc Tukey’s test **P < 0.01; ***P < 0.001; ****P < 0.0001. P < 0.05 was considered significant.