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Dual TGF‐β and PD‐1 blockade synergistically enhances MAGE‐A3‐specific CD8 + T cell response in esophageal squamous cell carcinoma
Author(s) -
Chen Xinfeng,
Wang Liping,
Li Pupu,
Song Mengjia,
Qin Guohui,
Gao Qun,
Zhang Zhen,
Yue Dongli,
Wang Dan,
Nan Shufeng,
Qi Yu,
Li Feng,
Yang Li,
Huang Lan,
Zhang Mingzhi,
Zhang Bin,
Gao Yanfeng,
Zhang Yi
Publication year - 2018
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.31730
Subject(s) - cancer research , cytotoxic t cell , cd8 , tumor microenvironment , t cell , antigen , medicine , immunology , biology , immune system , in vitro , biochemistry
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.