@article{50f38825cf62434e80ef162cfc4a799a,
title = "Clinical significance of programmed death-1 and programmed death-ligand 1 expression in the tumor microenvironment of clear cell renal cell carcinoma",
abstract = "Recently, immunotherapy based on blocking immune checkpoints with programmed death-1 (PD-1) or PD-ligand 1 (PD-L1) Abs has been introduced for the treatment of advanced clear cell renal cell carcinoma (ccRCC), especially tumors resistant to vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF-TKIs), but the significance of their expression in the tumor microenvironment is unclear. We investigated these immune checkpoint markers in tumor cells and tumor-infiltrating immune cells (TIIC) in the tumor microenvironment of 100 untreated and 25 VEGF-TKI-treated primary ccRCC tissues. Upregulated expression of PD-1 and PD-L1 by TIIC, and PD-L1 by tumor cells was associated with the histological grade and unfavorable prognosis of RCC patients. High PD-1 and PD-L1 expression by TIIC was associated with a poorer response to VEGF-TKI, whereas PD-L1 expression by tumor cells did not affect the efficacy of the treatment. Furthermore, increased PD-1-positive TIIC and PD-L1-positive TIIC were observed in tumors treated with VEGF-TKIs compared with those in untreated tumors. Our data suggest that PD-1 and PD-L1 expression by TIIC in the tumor microenvironment is involved in treatment resistance, and that sequential therapy with immune checkpoint inhibitors could be a promising therapeutic strategy for ccRCC resistant to VEGF-TKI treatment.",
keywords = "PD-1, PD-L1, VEGF-TKI, renal cell carcinoma, tumor microenvironment",
author = "{the Japanese Society of Renal Cancer} and Shuji Mikami and Ryuichi Mizuno and Tsunenori Kondo and Nobuo Shinohara and Norio Nonomura and Seiichiro Ozono and Masatoshi Eto and Katsunori Tatsugami and Tatsuya Takayama and Hideyasu Matsuyama and Takeshi Kishida and Mototsugu Oya",
note = "Funding Information: The authors thank Mr. Kazunari Shibata, Department of Diagnostic Pathology, Keio University Hospital, for his technical assistance, and Professor Yutaka Kawakami and Dr. Tomonobu Fujita, Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, for their useful advices. This work was supported in part by a Grant-in-Aid for Scientific Research (C) (Nos. 16K08657 and 19K07468) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT) (S.M.), and a Grant-in-Aid for Scientific Research (C) (No. 17K11159) (R.M.) and a Grant-in-Aid for Scientific Research (B) (No. 15H04977) from MEXT (M.O.). Funding Information: Ryuichi Mizuno: honoraria from Bristol-Myers Squibb, Novartis, Ono Pharmaceutical, Pfizer; Tsunenori Kondo: honoraria from Pfizer, Novartis, Ono Pharmaceutical, Bayer Yakuhin; Nobuo Shinohara: honoraria from Ono Pharmaceutical, Pfizer, Novartis, Chugai Parmaceutical, GSK, Janssen, MSD, Bayer Yakuhin, Takeda Pharmaceutical; grants from Ono Pharmaceutical, Astellas, Taiho Yakuhin; Norio Nonomura: honoraria from Astellas, Pfizer, Takeda Pharmaceutical; grants from Astellas, Ishihara Sangyo, Novartis, Takeda Pharmaceutical, Taiho Pharmaceutical, Sanofi, Nippon Kayaku, Nippon Shinyaku, Pfizer; Masatoshi Eto: honoraria from MSD, Ono Pharmaceutical, Chugai Pharmaceutical, Novartis, Pfizer, Bristol-Meyers Squibb; grants from Astellas, Kissei Pharmaceutical, Sanofi, Ono Pharmaceutical, Takeda Pharmaceutical; Hideyasu Matsuyama: honoraria from Janssen, MSD; grants from Janssen, MSD, Pfizer, Bayer Yakuhin, Baxter, Kyowa Hakko Kirin, Sanofi, Astellas, Takeda Pharmaceutical; Mototsugu Oya: honoraria from Pfizer, Novartis, Bayer Yakuhin, Ono Pharmaceutical, Bristol-Myers Squibb. The other authors declare no conflict of interest for this article. Publisher Copyright: {\textcopyright} 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.",
year = "2019",
month = jun,
doi = "10.1111/cas.14019",
language = "English",
volume = "110",
pages = "1820--1828",
journal = "Cancer Science",
issn = "1347-9032",
publisher = "Wiley-Blackwell",
number = "6",
}