Clinical significance of programmed death-1 and programmed death-ligand 1 expression in the tumor microenvironment of clear cell renal cell carcinoma

Mikami, S.; Mizuno, R.; Kondo, T.; Shinohara, N.; Nonomura, N.; Ozono, S.; Eto, M.; Tatsugami, K.; Takayama, T.; Matsuyama, H.; Kishida, T.; Oya, M.

Cancer Science 110(6): 1820-1828


ISSN/ISBN: 1347-9032
PMID: 30972888
DOI: 10.1111/cas.14019
Accession: 066680077

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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.