Soluble Tim-3 serves as a tumor prognostic marker and therapeutic target for CD8+ T cell exhaustion and anti-PD-1 resistance
Chaojia Chen, Fangcheng Zhao, Jiali Peng, Di Zhao, Liyun Xu, Huayu Li, Shuaiya Ma, Xueqi Peng, Xue Sheng, Yang Sun, Tixiao Wang, Haoqing Dong, Yuming Ding, Zhuanchang Wu, Xiaohong Liang, Lifen Gao, Hongyan Wang, Chunhong Ma, Chunyang Li
Abstract
Resistance to PD-1 blockade in onco-immunotherapy greatly limits its clinical application. T cell immunoglobulin 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 resistance. 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 overexpression 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 humanized 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. • Patients with tumors resistant to anti-PD-1 therapy exhibit high serum sTim-3 levels • sTim-3 promotes tumor progression and confers anti-PD-1 resistance in tumor models • sTim-3 promotes CD8 + T cell exhaustion and resistance to PD-1 blockade through CEACAM-1 • The ADAM10 inhibitor suppresses tumor progression and reverses anti-PD-1 resistance Tim-3 is a promising immune checkpoint in tumor immunotherapy. Chen et al. demonstrate that soluble Tim-3 (sTim-3) is a potential marker of tumor prognosis and resistance to anti-PD-1 therapy. sTim-3 exacerbates CD8 + T cell exhaustion and inhibits response to anti-PD-1 treatment, suggesting sTim-3 as a target to enhance tumor immunotherapy.