Clinicopathologic Analysis of PD-L1 and PD-L2 Expression in Renal Cell Carcinoma: Association with Oncogenic Proteins Status

Immune checkpoint blockade therapy targeting programmed death (PD)-1 or PD-ligand1 (L1) has shown promising results in renal cell carcinoma (RCC); however, the prognostic implications and clinicopathological features of PD-L1 and PD-L2 expression in RCC remain unclear. PD-L1 and PD-L2 expression was immunohistochemically evaluated in 425 resected RCCs of variable histologic subtypes and analyzed according to the clinicopathological status and oncogenic proteins status. PD-L1 expression was observed in 9.4 % with no difference between histologic subtypes, but PD-L2 was observed in 49.6 % with highest frequency in papillary RCC (PRCC) (P < 0.001). In clear cell RCC (CCRCC), PD-L1 expression was associated with adverse features, including higher nuclear grade, necrosis, sarcomatoid transformation, c-MET expression (all, P < 0.001) and VEGF expression (P = 0.002), whereas PD-L2 expression was related with c-MET and VEGF expression (P = 0.008 and P < 0.001). In PRCC, positive correlations between PD-L1 and EGFR expression (P = 0.007) or between PD-L2 and VEGF expression (P < 0.001) were observed. In CCRCC, PD-L1 and PD-L2 positivity were significantly associated with shorter progression-free survival (P < 0.001; P = 0.033) and cancer-specific survival (P < 0.001; P = 0.010), but not in PRCC. PD-L1 and PD-L2 expression predict poor prognosis in CCRCC. Thus, PD-1/PD-L pathway-targeted immunotherapy may be useful for treatment of patients with CCRCC.