Tim-3 mediates T cell trogocytosis to limit antitumor immunity
Ornella Pagliano, … , Pavel Strop, Hassane M. Zarour
Ornella Pagliano, … , Pavel Strop, Hassane M. Zarour
Published March 22, 2022
Citation Information: J Clin Invest. 2022;132(9):e152864. https://doi.org/10.1172/JCI152864.
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Tim-3 mediates T cell trogocytosis to limit antitumor immunity

Abstract

T cell immunoglobulin mucin domain-containing protein 3 (Tim-3) negatively regulates innate and adaptive immunity in cancer. To identify the mechanisms of Tim-3 in cancer immunity, we evaluated the effects of Tim-3 blockade in human and mouse melanoma. Here, we show that human programmed cell death 1–positive (PD-1+) Tim-3+CD8+ tumor-infiltrating lymphocytes (TILs) upregulate phosphatidylserine (PS), a receptor for Tim-3, and acquire cell surface myeloid markers from antigen-presenting cells (APCs) through transfer of membrane fragments called trogocytosis. Tim-3 blockade acted on Tim-3+ APCs in a PS-dependent fashion to disrupt the trogocytosis of activated tumor antigen–specific CD8+ T cells and PD-1+Tim-3+ CD8+ TILs isolated from patients with melanoma. Tim-3 and PD-1 blockades cooperated to disrupt trogocytosis of CD8+ TILs in 2 melanoma mouse models, decreasing tumor burden and prolonging survival. Deleting Tim-3 in dendritic cells but not in CD8+ T cells impeded the trogocytosis of CD8+ TILs in vivo. Trogocytosed CD8+ T cells presented tumor peptide–major histocompatibility complexes and became the target of fratricide T cell killing, which was reversed by Tim-3 blockade. Our findings have uncovered a mechanism Tim-3 uses to limit antitumor immunity.

Authors

Ornella Pagliano, Robert M. Morrison, Joe-Marc Chauvin, Hridesh Banerjee, Diwakar Davar, Quanquan Ding, Tokiyoshi Tanegashima, Wentao Gao, Saranya R. Chakka, Richelle DeBlasio, Ava Lowin, Kevin Kara, Mignane Ka, Bochra Zidi, Rada Amin, Itay Raphael, Shuowen Zhang, Simon C. Watkins, Cindy Sander, John M. Kirkwood, Marcus Bosenberg, Ana C. Anderson, Vijay K. Kuchroo, Lawrence P. Kane, Alan J. Korman, Arvind Rajpal, Sean M. West, Minhua Han, Christine Bee, Xiaodi Deng, Xiao Min Schebye, Pavel Strop, Hassane M. Zarour

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Figure 1

PD-1+Tim-3hi CD8+ TILs express myeloid markers acquired from APCs via trogocytosis in metastatic melanoma.

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PD-1+Tim-3hi CD8+ TILs express myeloid markers acquired from APCs via tr...
(A) Summary data (n = 20) showing expression of PD-1 and Tim-3 on CD8+ TILs in metastatic melanoma (MM). (B) Summary data showing frequencies of perforin+ (n = 16), CD107a+ (n = 24), and PS+ (n = 13) CD8+ TILs in MM according to PD-1 and Tim-3 expression. (C) Pooled data (n = 11) showing the correlation between CD107a and PS expression in PD-1+Tim-3hi CD8+ TILs in MM. (D) Representative dot plots (left) and summary data (right, n = 10) showing frequencies of CD11c+, CD14+, and PD-L1+ CD8+ TILs according to PD-1 and Tim-3 expression. (E) Confocal micrographs of PKH67+ PD-1+Tim-3– and PD-1+Tim-3hi CD8+ TILs coincubated for 30 minutes with autologous PKH26+CD45+CD3– cells. (F) Representative ImageStream analysis (upper) and summary data of cell frequencies with flow cytometry (lower, n = 8) showing cell surface coexpression of PKH26 and CD11c, CD14, or PD-L1 on PKH67+ PD-1+Tim-3– and PD-1+Tim-3hi CD8+ TILs after 30 minutes’ incubation with autologous PKH26+CD45+CD3– cells. P values were obtained by 1-way ANOVA followed by Holm-Šídák multiple comparisons test and Friedman’s test followed by Dunn’s multiple-comparison test (B), simple linear regression test (C), and paired t test and Wilcoxon’s matched pairs signed-rank test (D and F). *P < 0.05; **P < 0.01; ****P < 0.0001. Data indicate mean ± SD.