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

Ann Surg Oncol. 2016 Feb;23(2):694-702. doi: 10.1245/s10434-015-4903-7.


Background: Immune checkpoint blockade therapy targeting programmed death (PD)-1 or PD-ligand 1 (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.

Methods: 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.

Results: 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 PDL2 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.

Conclusions: 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.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • B7-H1 Antigen / metabolism*
  • Biomarkers, Tumor / metabolism*
  • Carcinoma, Papillary / metabolism
  • Carcinoma, Papillary / secondary*
  • Carcinoma, Renal Cell / metabolism
  • Carcinoma, Renal Cell / secondary*
  • ErbB Receptors / metabolism
  • Female
  • Follow-Up Studies
  • Humans
  • Immunoenzyme Techniques
  • Kidney Neoplasms / metabolism
  • Kidney Neoplasms / pathology*
  • Lymphatic Metastasis
  • Male
  • Middle Aged
  • Neoplasm Grading
  • Neoplasm Invasiveness
  • Prognosis
  • Programmed Cell Death 1 Ligand 2 Protein / metabolism*
  • Proto-Oncogene Proteins c-met / metabolism
  • Survival Rate
  • Vascular Endothelial Growth Factor A / metabolism
  • Young Adult


  • B7-H1 Antigen
  • Biomarkers, Tumor
  • CD274 protein, human
  • PDCD1LG2 protein, human
  • Programmed Cell Death 1 Ligand 2 Protein
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • EGFR protein, human
  • ErbB Receptors
  • Proto-Oncogene Proteins c-met