Inverse association between programmed death ligand 1 and genes in the VEGF pathway in primary clear cell renal cell carcinoma

Richard W. Joseph, Mansi Parasramka, Jeanette E. Eckel-Passow, Dan Serie, Kevin Wu, Liuyan Jiang, Krishna Kalari, R. Houston Thompson, Thai Huu Ho, Erik P. Castle, John Cheville, Eugene D. Kwon, E. Aubrey Thompson, Alexander Parker

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


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 = -0.23; P = 0.01), VEGFR1 (r = -0.34; P < 0.001), and VEGFR2 (r = -0.23; P = 0.01). When dichotomized, the PDL-1-positive cohort trended toward a lower expression of VEGFA (fold change = 0.72; P = 0.056) and VEGFR1 (fold change = 0.69; P = 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 = 0.25; P = 0.015), and there was a trend toward an inverse relationship between TIL and VEGFA gene expression (r = -0.18; P = 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.

Original languageEnglish (US)
Pages (from-to)378-385
Number of pages8
JournalCancer Immunology Research
Issue number6
StatePublished - Dec 1 2013

ASJC Scopus subject areas

  • Immunology
  • Cancer Research


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