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.
View: Text | PDF
Research Article Immunology Oncology

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

×

Figure 4

Tim-3 blockade acts in APCs in a PS-mediated fashion and cooperates with PD-1 blockade to decrease trogocytosis of TA-specific CD8+ T cells.

Options: View larger image (or click on image) Download as PowerPoint
Tim-3 blockade acts in APCs in a PS-mediated fashion and cooperates with...
(A and B) Representative flow cytometry dot plots (A) and summary data (B) evaluating PKH26 and PS expression by CD8+ T cells. PKH26+HLA-A2+ DCs were incubated with indicated antibodies, then added to wells with NY-ESO-1 157-165–specific clone 95/3 and cognate peptide for 5 days before flow cytometry (A, upper); CD8+ T cell clone 95/3 was incubated with indicated antibodies, then added to wells with PKH26+HLA-A2+ DCs pulsed with cognate peptide for 5 days before flow cytometry (A, lower). Summary data showing fold changes of PKH26+ and PS+ CD8+ T cells upon DC blockade (B, upper) or CD8+ T cell blockade (B, lower) as compared with IgG mAbs. Data shown are representative of 3 independent experiments. (C) Representative ImageStream images (left) and flow cytometry analysis of PKH26+ CD8+ T cells (middle and right panels). PKH67+ PD-1+Tim-3– and PD-1+Tim-3+ CD8+ TILs were incubated for 30 minutes with PKH26+CD45+CD3– cells isolated from MM in the presence of indicated antibodies before analysis. Representative summary data showing fold change of PKH26+ PD-1+Tim-3+ CD8+ TILs in wells with aTim-3.18 or aPD-1 as compared with IgG control (n = 5). P values shown (B and C) were obtained from paired t tests in Supplemental Figure 3, A and B. Data indicate mean ± SD.