Document Type
Article
Publication Date
8-20-2024
Original Citation
Chen C,
Zhao F,
Peng J,
Zhao D,
Xu L,
Li H,
Ma S,
Peng X,
Sheng X,
Sun Y,
Wang T,
Dong H,
Ding Y,
Wu Z,
Liang X,
Gao L,
Wang H,
Ma C,
Li C.
Soluble Tim-3 serves as a tumor prognostic marker and therapeutic target for CD8 Cell Rep Med. 2024;5(8):101686.
Keywords
Hepatitis A Virus Cellular Receptor 2, Humans, Animals, CD8-Positive T-Lymphocytes, Drug Resistance, Neoplasm, Mice, Programmed Cell Death 1 Receptor, Prognosis, Biomarkers, Tumor, Immune Checkpoint Inhibitors, Cell Line, Tumor, Female, Male, Lung Neoplasms, Carcinoma, Non-Small-Cell Lung, ADAM10 Protein, Mice, Inbred C57BL, T-Cell Exhaustion
JAX Source
Cell Rep Med. 2024;5(8):101686.
ISSN
2666-3791
PMID
39168104
DOI
https://doi.org/10.1016/j.xcrm.2024.101686
Abstract
Resistance to PD-1 blockade in onco-immunotherapy greatly limits its clinical application. T cell immuno- globulin and mucin domain containing-3 (Tim-3), a promising immune checkpoint target, is cleaved by ADAM10/17 to produce its soluble form (sTim-3) in humans, potentially becoming involved in anti-PD-1 resis- tance. Herein, serum sTim-3 upregulation was observed in non-small cell lung cancer (NSCLC) and various digestive tumors. Notably, serum sTim-3 is further upregulated in non-responding patients undergoing anti- PD-1 therapy for NSCLC and anti-PD-1-resistant cholangiocarcinoma patients. Furthermore, sTim-3 overex- pression facilitates tumor progression and confers anti-PD-1 resistance in multiple tumor mouse models. Mechanistically, sTim-3 induces terminal T cell exhaustion and attenuates CD8 + T cell response to PD-1 blockade through carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1). Moreover, the ADAM10 inhibitor GI254023X, which blocks sTim-3 production, reduces tumor progression in Tim-3 human- ized mice and reverses anti-PD-1 resistance in human tumor-infiltrating lymphocytes (TILs). Overall, human sTim-3 holds great predictive and therapeutic potential in onco-immunotherapy.
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