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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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

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Figure 9

Trogocytosed CD8+ T cells become the target of fratricide killing.

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Trogocytosed CD8+ T cells become the target of fratricide killing. (A) F...
(A) Flow cytometry data showing fratricide killing of PD-1+Tim-3+ CD8+ TILs isolated from human or mouse melanoma. PD-1+Tim-3– TILs sorted from human MM or YUMMER 1.7 (day 21 postimplantation) were labeled with PKH67 and cocultured with autologous PKH26-labeled PD-1–Tim-3– (group “A” in the figure) or PD-1+Tim-3+ (group “B” in the figure) CD8+ TILs before flow cytometry (left). Representative dot plots (middle) and summary data (right, n = 6) showing percentages of PKH67+CD107a+ CD8+ TILs. (B) Flow cytometry data showing that Tim-3 blockade impedes fratricide killing of NY-ESO-1–specific CD8+ T cells in vitro. DCs obtained from HLA-A2+ HDs were pulsed with either tumor lysate (T. Lysate) from an HLA2/NY-ESO-1+ melanoma cell line, MEL 285, or NY-ESO-1 157-165 peptide (NY-ESO-1) with aTim-3 or IgG control mAbs, then washed and cocultured with PKH26-labeled clone 95/3. PKH26+CD8+ T cells were sorted and coincubated with PKH67+ clone 95/3 for 6 hours before flow cytometry (left). Representative dot plots (middle) showing percentages of PKH67+PKH26–CD11c+ and PKH67+PKH26–CD107a+ CD8+ T cell clones and summary data of frequency fold changes upon aTim-3 as compared with IgG control mAbs (right, n = 6). Data are representative of 3 independent experiments. P values were obtained by paired t test (A). P values shown in B were obtained from paired t tests in Supplemental Figure 5B. ***P < 0.001; ****P < 0.0001. Data indicate mean ± SD.