Co-Regulation of Immune Checkpoint PD-L1 with Interferon-Gamma Signaling is Associated with a Survival Benefit in Renal Cell Cancer

Background 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. Objective To evaluate PD-L1 expression and its dependence on interferon-gamma (IFN-gamma) in RCC cell lines and tissues in relation to disease outcome. Methods and Patients 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-gamma 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. Results In ccRCC-like cell lines, PD-L1 was induced by canonical IFN-gamma signaling, whereas in a pRCC-like cell line, PD-L1 was refractory towards IFN-gamma signaling. In ccRCC and SKCM tissues, GSEA revealed significant IFN-gamma 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. Conclusions The findings suggest that ccRCC and pRCC differ with respect to PD-L1 regulation by IFN-gamma-signaling. High PD-L1-mRNA levels in tumor tissues with a positive IFN-gamma signature favorably affect OS and DFS.