Independent association of PD-L1 expression with noninactivated VHL clear cell renal cell carcinoma-A finding with therapeutic potential.

Clear cell renal cell carcinoma (ccRCC) is an aggressive tumor that is characterized in most cases by inactivation of the tumor suppressor gene VHL. The VHL/HIF/VEGF pathway thus plays a major role in angiogenesis and is currently targeted by anti-angiogenic therapy. The emergence of resistance is leading to the use of targeted immunotherapy against immune checkpoint PD1/PDL1 that restores antitumor immune response. The correlation between VHL status and PD-L1 expression has been little investigated. In this study, we retrospectively reviewed 98 consecutive cases of ccRCC and correlated PD-L1 expression by immunohistochemistry (IHC) with clinical data (up to 10-year follow-up), pathological criteria, VEGF, PAR-3, CAIX and PD-1 expressions by IHC and complete VHL status (deletion, mutation and promoter hypermethylation). PD-L1 expression was observed in 69 ccRCC (70.4%) and the corresponding patients had a worse prognosis, with a median specific survival of 52 months (p=0.03). PD-L1 expression was significantly associated with poor prognostic factors such as a higher ISUP nucleolar grade (p=0.01), metastases at diagnosis (p=0.01), a sarcomatoid component (p=0.04), overexpression of VEGF (p<0.01), and cytoplasmic PAR-3 expression (p=0.01). PD-L1 expression was also associated with dense PD-1 expression (p=0.007) and with ccRCC with 0 or 1 alteration(s) (non-inactivated VHL tumors) (p<0.01) that remained significant after multivariate analysis (p=0.004 and p=0.024, respectively). Interestingly, all wild-type VHL tumors (no VHL gene alteration, 11.2%) expressed PD-L1. In this study, we found PD-L1 expression to be associated with non-inactivated VHL tumors and in particular wild-type VHL ccRCC which may benefit from therapies inhibiting PD-L1/PD-1. This article is protected by copyright. All rights reserved.