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Annals of Surgical Oncology
Published in: Annals of Surgical Oncology 13/2023

21-08-2023 | Gastric Cancer | Translational Research

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

Authors: 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

Published in: Annals of Surgical Oncology | Issue 13/2023

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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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Metadata
Title
Effects of TRPV2 on the Expression of PD-L1 and Its Binding Ability to PD-1 in Gastric Cancer
Authors
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
Publication date
21-08-2023
Publisher
Springer International Publishing
Published in
Annals of Surgical Oncology / Issue 13/2023
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-023-14084-0

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