PD-1 is highly expressed on tumor-infiltrated antigen-specific T cells and limit the antitumor function. Blocking of PD-1/PD-L1 signaling has shown unprecedented curative efficacies in patients with advanced cancer. However, only a limited population of patients benefited from such therapies. Our study aimed to explore biological properties, functional regulation and reversal of MAGE-A3-specific CD8⁺ T cells in patients with esophageal squamous cell carcinoma (ESCC). The underlying principle of deficiency and restoring MAGE-A3-specific CD8⁺ T cells function in tumor microenvironment (TME) was evaluated. MAGE-A3-specific CD8⁺ T cells could lyse HLA-A2⁺ /MAGE-A3⁺ tumor cells. Tetramer⁺ T cell frequency was higher in elder patients, but lower in patients with lymph node metastasis and late tumor stage (p < 0.05). CD107a^high expression on functional T cells was an independent prognostic factor in Cox regression analysis. PD-1 was highly expressed on dysfunctional antigen-specific CD8⁺ T cells and tumor infiltrating T lymphocytes (p < 0.05). Myeloid-derived suppressor cells (MDSCs) derived-TGF-β mediated PD-1^high expression on CD8⁺ T cells, which led to be resistance to PD-1/PD-L1 blockade in TME. Dual PD-1/PD-L1 and TGF-β signaling pathway blockades synergistically restored the function and antitumor ability of antigen-specific CD8⁺ T cells in vitro/vivo assay. The presence of functional MAGE-A3-specific CD8⁺ T cells had an independent prognostic impact on survival of patients with ESCC. Furthermore, MDSCs-derived TGF-β increased PD-1 expression on T cells and decreased the sensitivity to PD-1/PD-L1 blockade. Combining T cell-based therapy with dual PD-1/PD-L1 and TGF-β signaling pathway blockade could be considered a promising strategy for cancer treatment.

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