Immune suppression caused by PD-L2 expression on tumor cells in gastric cancer
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ORIGINAL ARTICLE
Immune suppression caused by PD‑L2 expression on tumor cells in gastric cancer Yuko Nakayama1,2 · Kosaku Mimura1,3,4,5 · Ley‑Fang Kua6 · Hirokazu Okayama1 · Aung Kyi Thar Min1 · Katsuharu Saito1 · Hiroyuki Hanayama1 · Yohei Watanabe1 · Motonobu Saito1 · Tomoyuki Momma1 · Zenichiro Saze1 · Shinji Ohki1 · Yoshiyuki Suzuki7 · Daisuke Ichikawa2 · Wei‑Peng Yong6,8 · Koji Kono1 Received: 20 January 2020 / Accepted: 23 April 2020 © The International Gastric Cancer Association and The Japanese Gastric Cancer Association 2020
Abstract Background Gastric cancer (GC) patients with PD-L1-negative tumor occasionally have a favorable response to anti-PD-1 mAb. The aim of the present study was to investigate the regulatory mechanism and immunosuppressive role of PD-L2 in GC. Methods We used immunohistochemistry to evaluate the expression of PD-L2 in primary tumors from 194 patients with GC. The mechanism of PD-L2 expression was assessed in TCGA stomach adenocarcinoma tissue dataset and in vitro assay using GC cell lines. The immunosuppressive role of PD-L2 was evaluated by cytotoxicity of CTL clone against PD-L2 expressing GC cells. Results PD-L2 was expressed on tumor cells (TCs) of 28.4% patients and PD-L2 expression on TCs was significantly associated with tumor progression. TCGA dataset revealed that IFN-γ and, to a lesser extent, IL-4 signature significantly correlated with PD-L2 expression. In vitro assay showed that IFN-γ and, also to a lesser extent, IL-4 can upregulate PD-L2 expression on GC cells. Anti-PD-L2 mAb significantly enhanced the cytotoxicity of CTL clone against GC cell lines expressing PD-L2. Conclusions PD-L2 is expressed on GC cells and PD-1/PD-L2 interaction are functionally involved in anti-tumor CTL activities. PD-L2 expression should be considered when determining the optimal immunotherapy for GC. Keywords Gastric cancer · PD-L2 · PD-L1 · Immunotherapy · Cytotoxic T lymphocyte
Background
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10120-020-01079-z) contains supplementary material, which is available to authorized users. * Kosaku Mimura [email protected] 1
Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima‑city, Fukushima 960‑1295, Japan
2
First Department of Surgery, Faculty of Medicine, University of Yamanashi, Chuo‑city, Yamanashi 409‑3898, Japan
3
Department of Blood Transfusion and Transplantation Immunology, Fukushima Medical University School of Medicine, Fukushima, Fukushima 960‑1295, Japan
4
Department of Advanced Cancer Immunotherapy, Fukushima Medical University School of Medicine, Fukushima, Fukushima 960‑1295, Japan
Gastric cancer (GC) is the fifth most frequently diagnosed cancer and the third leading cause of cancer death in the world, accounting for over 1,000,000 new cases and 783,000 deaths in 2018 worldwide [1]. Especially in 5
Department of Progressive DOHaD Research, Fukushima Medical University School of Medi
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