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Effects of TRPV2 on the Expression of PD-L1 and Its Binding Ability to PD-1 in Gastric Cancer

  • Translational Research
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Transient receptor potential vanilloid 2 (TRPV2) is a member of the TRP superfamily of non-specific cation channels with functionally diverse roles. We herein investigated the effects of TRPV2 on the expression of programmed cell death-ligand 1 (PD-L1) and its binding ability to programmed cell death-1 (PD-1) in gastric cancer (GC).

Methods

Knockdown (KD) experiments were performed on human GC cell lines using TRPV2 small-interfering RNA. The surface expression of PD-L1 and its binding ability to PD-1 were analyzed by flow cytometry. Eighty primary tissue samples were assessed by immunohistochemistry (IHC), and the relationships between IHC results, clinicopathological factors, and patient prognosis were analyzed. The molecular mechanisms underlying the effects of TRPV2 on the intracellular ion environment were also investigated.

Results

TRPV2-KD decreased the expression level of PD-L1 in NUGC4 and MKN7 cells, thereby inhibiting its binding to PD-1. A survival analysis revealed that 5-year overall survival rates were significantly lower in the TRPV2 high expression and PD-L1-positive groups. In IHC multivariate analysis of GC patients, high TRPV2 expression was identified as an independent prognostic factor. Furthermore, a positive correlation was observed between the expression of TRPV2 and PD-L1. An immunofluorescence analysis showed that TRPV2-KD decreased the intracellular concentration of calcium ([Ca2+]i). Treatment with ionomycin/PMA (phorbol 12-myristate 13-acetate), which increased [Ca2+]i, upregulated the protein expression of PD-L1 and promoted its binding to PD-1.

Conclusions

The surface expression of PD-L1 and its binding ability to PD-1 in GC were regulated by TRPV2 through [Ca2+]i, indicating the potential of TRPV2 as a biomarker and target of immune checkpoint blockage for GC.

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Acknowledgments

The present study was supported by Grants-in-Aid for Scientific Research (C) [20K09016, 20K09084, 22K08832, and 21K08689] and Grants-in-Aid for Young Scientists [20K17659, 21K16456, and 22K16518] from the Japan Society for the Promotion of Science.

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Author notes

  1. Atsushi Shiozaki and Tomoyuki Fukami have contributed equally to this study.

Authors and Affiliations

  1. Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Atsushi Shiozaki MD, PhD, Tomoyuki Fukami MD, PhD, Hiroki Shimizu MD, PhD, Toshiyuki Kosuga MD, PhD, Michihiro Kudou MD, PhD, Kenichi Takemoto MD, PhD, Keita Katsurahara MD, PhD, Keiji Nishibeppu MD, PhD, Takuma Ohashi MD, PhD, Tomohiro Arita MD, PhD, Hirotaka Konishi MD, PhD, Shuhei Komatsu MD, PhD, Takeshi Kubota MD, PhD, Hitoshi Fujiwara MD, PhD & Eigo Otsuji MD, PhD

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  1. Atsushi Shiozaki MD, PhD
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Corresponding author

Correspondence to Atsushi Shiozaki MD, PhD.

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Atsushi Shiozaki, Tomoyuki Fukami, Hiroki Shimizu, Toshiyuki Kosuga, Michihiro Kudou, Kenichi Takemoto, Keita Katsurahara, Keiji Nishibeppu, Takuma Ohashi, Tomohiro Arita, Hirotaka Konishi, Shuhei Komatsu, Takeshi Kubota, Hitoshi Fujiwara, and Eigo Otsuji have no conflicts of interest or financial ties to declare.

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Shiozaki, A., Fukami, T., Shimizu, H. et al. Effects of TRPV2 on the Expression of PD-L1 and Its Binding Ability to PD-1 in Gastric Cancer. Ann Surg Oncol 30, 8704–8716 (2023). https://doi.org/10.1245/s10434-023-14084-0

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