Clinical significance of PD-1 and PD-L1 expression in the tumor microenvironment of clear cell renal cell carcinoma.

Recently, immunotherapy based on blocking immune checkpoints with programmed death-1 (PD-1) or PD-ligand 1 (PD-L1) antibodies 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 may be a promising therapeutic strategy for ccRCC resistant to VEGF-TKI treatment. This article is protected by copyright. All rights reserved.

Cancer science. 2019 Apr 10 [Epub ahead of print]

Shuji Mikami, Ryuichi Mizuno, Tsunenori Kondo, Nobuo Shinohara, Norio Nonomura, Seiichiro Ozono, Masatoshi Eto, Katsunori Tatsugami, Tatsuya Takayama, Hideyasu Matsuyama, Takeshi Kishida, Mototsugu Oya, Japanese Society of Renal Cancer

Department of Diagnostic Pathology, Keio University School of Medicine., Department of Urology, Keio University School of Medicine, Tokyo., Department of Urology, Tokyo Women's Medical University, Medical Center East, Tokyo., Department of Genitourinary Surgery, Hokkaido University Graduate School of Medicine, Sapporo., Department of Urology, Osaka University School of Medicine, Osaka., Department of Urology, Hamamatsu University School of Medicine, Hamamatsu., Department of Urology, Graduate School of Medical Science, Kyushu University, Fukuoka., Department of Urology, Jichi Medical University, Shimotsuke., Department of Urology, Graduate School of Medicine, Yamaguchi University, Ube., Department of Urology, Kanagawa Cancer Center, Yokohama, Japan.