Yuko Nakayama1,2, Kosaku Mimura3,4,5,6, Ley-Fang Kua7, Hirokazu Okayama1, Aung Kyi Thar Min1, Katsuharu Saito1, Hiroyuki Hanayama1, Yohei Watanabe1, Motonobu Saito1, Tomoyuki Momma1, Zenichiro Saze1, Shinji Ohki1, Yoshiyuki Suzuki8, Daisuke Ichikawa2, Wei-Peng Yong7,9, Koji Kono1. 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 Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima-city, Fukushima, 960-1295, Japan. kmimura@fmu.ac.jp. 4. Department of Blood Transfusion and Transplantation Immunology, Fukushima Medical University School of Medicine, Fukushima, Fukushima, 960-1295, Japan. kmimura@fmu.ac.jp. 5. Department of Advanced Cancer Immunotherapy, Fukushima Medical University School of Medicine, Fukushima, Fukushima, 960-1295, Japan. kmimura@fmu.ac.jp. 6. Department of Progressive DOHaD Research, Fukushima Medical University School of Medicine, Fukushima, Fukushima, 960-1295, Japan. kmimura@fmu.ac.jp. 7. Department of Haematology-Oncology, National University Health System, Singapore, 119228, Singapore. 8. Department of Radiation Oncology, Fukushima Medical University School of Medicine, Fukushima, Fukushima, 960-1295, Japan. 9. Cancer Science Institute, National University of Singapore, Singapore, 117599, Singapore.
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.
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.
Entities:
Keywords:
Cytotoxic T lymphocyte; Gastric cancer; Immunotherapy; PD-L1; PD-L2