1. Academic Validation
  2. PD-1 does not mark tumor-infiltrating CD8+ T cell dysfunction in human gastric cancer

PD-1 does not mark tumor-infiltrating CD8+ T cell dysfunction in human gastric cancer

  • J Immunother Cancer. 2020 Aug;8(2):e000422. doi: 10.1136/jitc-2019-000422.
Yang Shen  # 1 2 Yongsheng Teng  # 1 Yipin Lv 1 Yongliang Zhao 3 Yuan Qiu 4 Weisan Chen 5 Lina Wang 1 Ying Wang 1 Fangyuan Mao 1 Ping Cheng 1 Daiyuan Ma 6 Yuan Zhuang 7 Quanming Zou 7 Liusheng Peng 7
Affiliations

Affiliations

  • 1 National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing, China.
  • 2 Department of oncology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan Province, China.
  • 3 Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China.
  • 4 Department of General Surgery of Xinqiao Hospital, Third Military Medical University, Chongqing, China.
  • 5 La Trobe Institute for Molecular Science, School of Molecular Science, La Trobe University, Bundoora, Victoria, Australia.
  • 6 Department of oncology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan Province, China pengliusheng06@163.com qmzou@tmmu.edu.cn yuanzhuang1983@yahoo.com mdylx@163.com.
  • 7 National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing, China pengliusheng06@163.com qmzou@tmmu.edu.cn yuanzhuang1983@yahoo.com mdylx@163.com.
  • # Contributed equally.
Abstract

Background: Overexpression of programmed cell death protein 1 (PD-1) is linked to CD8+ T cell dysfunction and contributes to tumor immune escape. However, the prevalence and functional regulations of PD-1 expression on CD8+ T cells in human gastric Cancer (GC) remain largely unknown.

Methods: Flow cytometry was performed to analyze the level, phenotype, functional and clinical relevance of PD-1+CD8+ T cells in GC patients. Peripheral blood CD8+ T cells were purified and subsequently exposed to culture supernatants from digested primary GC tumor tissues (TSN) in vitro for PD-1 expression and functional assays. Tumor responses to adoptively transferred TSN-stimulated CD8+ T cells or to the TSN-stimulated CD8+ T cell transfer combined with an anti-PD-1 antibody injection were measured in an in vivo xenograft mouse model.

Results: GC patients' tumors showed a significantly increased PD-1+CD8+ T cell infiltration. However, these GC-infiltrating PD-1+CD8+ T cells showed equivalent function to their PD-1-CD8+ counterparts and they did not predict tumor progression. High level of transforming growth factor-β1 (TGF-β1) in tumors was positively correlated with PD-1+CD8+ T cell infiltration, and in vitro GC-derived TGF-β1 induced PD-1 expression on CD8+ T cells via SMAD3 signaling, whereas SMAD2 signaling was involved in GC-derived TGF-β1-mediated CD8+ T cell dysfunction. Furthermore, GC-derived TGF-β1-mediated CD8+ T cell dysfunction contributed to tumor growth in vivo that could not be attenuated by PD-1 blockade.

Conclusions: Our data highlight that GC-derived TGF-β1 promotes PD-1 independent CD8+ T cell dysfunction. Therefore, restoring CD8+ T cell function by a combinational PD-1 and TGF-β1 blockade might benefit future GC immunotherapy.

Keywords

gastroenterology; immunology; tumours.

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