Priority Brief Inverse Association between Programmed Death Ligand 1 and Genes in the VEGF Pathway in Primary Clear Cell Renal Cell Carcinoma

Increased angiogenesis and tumor-induced immune evasion are two mechanisms by which clear cell renal cell carcinoma (ccRCC) proliferate and metastasize; however, the relationship between these pathways in human ccRCC is poorly understood. We conducted a nested case–control study using 98 archived tumor samples from patients diagnosed with primary ccRCC between 1990 and 2006, half of which were identified by immunohistochemistry (IHC) as either programmed death ligand 1 (PDL-1)–positive or PDL-1–negative. RNAs were extracted from the formalin-fixed paraffin-embedded tumor slides and the expression of the VEGFA, VEGFR1, VEGFR2, and PDL-1 genes was quantified. We assessed the presence of tumor-infiltrating lymphocytes (TIL) by IHC for CD3, and then analyzed the relationship among VEGFA, VEGFR1, VEGFR2, CD3, and PDL-1. When analyzed as a continuous variable, PDL-1 protein expression by IHC inversely correlates with the expression of the three VEGF-related genes: VEGFA (r 1⁄4 0.23; P 1⁄4 0.01), VEGFR1 (r 1⁄4 0.34; P < 0.001), and VEGFR2 (r 1⁄4 0.23; P 1⁄4 0.01). When dichotomized, the PDL-1–positive cohort trended toward a lower expression of VEGFA (fold change 1⁄4 0.72; P 1⁄4 0.056) and VEGFR1 (fold change 1⁄4 0.69; P 1⁄4 0.057). In addition, there was a significant and positive relationship between the presence of TIL as assessed by IHC for CD3 and PDL-1 by IHC (r 1⁄4 0.25; P 1⁄4 0.015), and there was a trend toward an inverse relationship between TIL and VEGFA gene expression (r 1⁄4 0.18; P 1⁄4 0.089). In conclusion, this is the first demonstration of an inverse association between the angiogenesis and PDL-1 pathways in tumor samples from primary ccRCC, and this relationship may be related to the immunosuppressive effects of VEGF signaling. Cancer Immunol Res; 1(6); 378–85. 2013 AACR.