Identification of Co-inhibitory Receptors PD-1 and TIM-3 on T Cells from Gastric Cancer Patients

The critical role of tumor antigen-specific immune responses to restrain tumor growth in patients with gastric cancer furthers the need to dissect the co-inhibitory pathways involved in tumor infiltrating lymphocyte (TIL) exhaustion/dysfunction. It was previously reported that PD-1 expression was significantly increased on CD4+ and CD8+ T cells from patients with gastric cancer and in gastric cancer tissues, compared to normal donors. In this study, we observed up-regulation of TIM-3 and PD-1 expression on peripheral T cells and up-regulation of CTLA-4, TIGIT, TIM-3 and PD-1 expression on TILs from gastric cancer patients. Furthermore, the percentages of PD-1+/TIM-3+ and PD-1+/TIM-3- peripheral T cells was significantly higher in gastric cancer patients than normal donors, and the percentage of PD-1+/TIM-3+ TILs was significantly higher than the percentage of PD-1+/TIM-3+ peripheral T cells in gastric cancer patients. PD-1+/TIM-3+ cells represent the predominant fraction of TILs. PD-1 blockade enhanced cytokine production and the cytotoxicity of TILs and exhibited a synergistic effect with TIM-3 blockade. Moreover, the expression of PD-1 was associated with the age, tumor size and lymph node metastasis of patients. Collectively, our results suggest that the use of anti-PD-1 blockade in combination with anti-TIM-3 blockade could restore the function of TILs in patients with gastric cancer.