Programmed death ligand (PD-L1)-based immune checkpoint blockade therapy for metastatic renal cell carcinoma (RCC) achieves significant response rates in a subgroup of patients. The relevance of PD-L1 gene regulation for disease outcome is not clear.
To evaluate PD-L1 expression and its dependence on interferon-γ (IFN-γ) in RCC cell lines and tissues in relation to disease outcome.
Regulation of PD-L1-mRNA and PD-L1 protein was studied in cell lines from clear cell RCC (ccRCC) and papillary RCC (pRCC) by quantitative RT-PCR and Western-blot analysis. PD-L1-mRNA correlation and gene-set enrichment analysis (GSEA) of the IFN-γ pathway were conducted with RNA-Seq from ccRCC, pRCC, and skin cutaneous melanoma (SKCM) tissue. In addition, patient overall survival (OS) and disease-free survival (DFS) (cBioPortal for Cancer Genomics) were considered.
In ccRCC-like cell lines, PD-L1 was induced by canonical IFN-γ signaling, whereas in a pRCC-like cell line, PD-L1 was refractory towards IFN-γ signaling. In ccRCC and SKCM tissues, GSEA revealed significant IFN-γ pathway activation in tissue samples with high PD-L1-mRNA levels. This was not observed in pRCC tissue. ccRCC and SKMC patients with low PD-L1-mRNA levels had significantly shorter OS and DFS than those with high PD-L1-mRNA levels. In pRCC patients, no significant difference in OS and DFS with regard to PD-L1-mRNA tissue levels was obvious.
The findings suggest that ccRCC and pRCC differ with respect to PD-L1 regulation by IFN-γ-signaling. High PD-L1-mRNA levels in tumor tissues with a positive IFN-γ signature favorably affect OS and DFS.
Targeted oncology. 2020 Jun 03 [Epub ahead of print]
Jörg Hänze, Moritz Wegner, Elfriede Noessner, Rainer Hofmann, Axel Hegele
Department of Urology and Pediatric Urology, Faculty of Medicine, Philipps-University Marburg, 35043, Baldingerstraße Marburg, Germany. ., Department of Urology and Pediatric Urology, Faculty of Medicine, Philipps-University Marburg, 35043, Baldingerstraße Marburg, Germany., Immunoanalytics Research Group Tissues Control of Immunocytes, Helmholtz Zentrum München, National Research Center for Environmental Health, Munich, Germany.