학술논문
Tim-3 mediates T cell trogocytosis to limit antitumor immunity
Document Type
article
Author
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
Source
The Journal of Clinical Investigation, Vol 132, Iss 9 (2022)
Subject
Language
English
ISSN
1558-8238
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.