Tim-3 mediates T cell trogocytosis to limit antitumor immunity

J Clin Invest. 2022 May 2;132(9):e152864. doi: 10.1172/JCI152864.


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.

Keywords: Cancer immunotherapy; Immunology; Melanoma; Oncology; T cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes
  • Hepatitis A Virus Cellular Receptor 2 / genetics
  • Hepatitis A Virus Cellular Receptor 2 / immunology*
  • Hepatitis A Virus Cellular Receptor 2 / metabolism
  • Humans
  • Lymphocytes, Tumor-Infiltrating
  • Melanoma* / pathology
  • Mice
  • Programmed Cell Death 1 Receptor
  • Trogocytosis


  • HAVCR2 protein, human
  • Hepatitis A Virus Cellular Receptor 2
  • Programmed Cell Death 1 Receptor