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

Xinfeng Chen, Liping Wang, Pupu Li, Mengjia Song, Guohui Qin, Qun Gao, Zhen Zhang, Dongli Yue, Dan Wang, Shufeng Nan, Yu Qi, Feng Li, Li Yang, Lan Huang, Mingzhi Zhang, Bin Zhang, Yanfeng Gao, Yi Zhang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

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). CD107ahigh 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-1high 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.

Original languageEnglish (US)
Pages (from-to)2561-2574
Number of pages14
JournalInternational Journal of Cancer
Volume143
Issue number10
DOIs
StatePublished - Nov 15 2018

Keywords

  • MAGE-A3
  • TGF-β
  • esophageal squamous cell carcinoma
  • myeloid-derived suppressor cells
  • programmed death receptor 1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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