Dual TGF‐β and PD‐1 blockade synergistically enhances MAGE‐A3‐specific CD8+ T cell response in esophageal squamous cell carcinoma

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.