Abstract
BackgroundClear cell renal cell carcinoma (ccRCC) is the most common renal malignancy. Hypoxia-inducible factors, HIF-1α and HIF-2α, are expressed in the majority of ccRCC. Targeting immune checkpoints with the blockade of PD-1 and its ligand PD-L1 reorganizes T-cell activity in tumor microenvironment and provides important antitumor responses. PD-L1 upregulation has been found to be hypoxia-inducible factor (HIF) dependent. Our aim is to demonstrate the association between PD-L1 and HIF expression and to reveal the role of PD-L1 in prognosis and its association with tumor microenvironment.MethodsSurgical specimens from 145 patients diagnosed with ccRCC, who had undergone radical or partial nephrectomy, were retrospectively analyzed. Immunohistochemistry on tissue microarrays (TMA) was performed to demonstrate expressions of PD-L1, HIF-1α, and HIF-2α in tumor cells and PD-1, CD4, and CD8 in lymphocytes to assess lymphocyte density in tumor microenvironment.ResultsPD-L1 tumor cell expression was detected in 20/125 (13.8%) cases, which correlated with higher levels of PD-1, CD4, CD8 and HIF-2α expression. Low or high expression of HIF-1α was similar in PD-L1-positive cases. When PD-L1-positive cases were compared with negative ones, there was no significant difference in terms of prognostic factors. However, the number of WHO/ISUP grade 3–4 tumors was significantly higher in PD-L1-positive cases than in negative ones.ConclusionPD-L1 tumor cell expression is strongly associated with increased HIF-2α expression and presence of dense lymphocytic infiltration in ccRCCs. Our findings confirm that PD-L1 positivity is associated with high ISUP nucleolar grade. The association between PD-L1, HIF, and lymphocyte density in tumor microenvironment must be clarified and especially taken into account in combination treatment.
Highlights
Clear cell renal cell carcinoma is the most common renal malignancy
This study aims to determine the correlation between the programmed death ligand 1 (PD-L1) tumor cell expression and clinicopathological prognostic factors, lymphocyte density displaying programmed cell death 1 (PD-1), CD4, and CD8 expression in the tumor microenvironment in Clear cell renal cell carcinoma (ccRCC) series
When PD-L1 exhibited positive results, the rate of dense lymphocytic infiltration staining with PD-1, CD4, and CD8 was significantly high (P < 0.05; Table 2; Fig. 1a–d)
Summary
Clear cell renal cell carcinoma (ccRCC) is the most common renal malignancy. Hypoxia-inducible factors, HIF-1α and HIF-2α, are expressed in the majority of ccRCC. Targeting immune checkpoints with the blockade of PD-1 and its ligand PD-L1 reorganizes T-cell activity in tumor microenvironment and provides important antitumor responses. PD-L1 upregulation has been found to be hypoxia-inducible factor (HIF) dependent. Clear cell renal cell carcinoma (ccRCC) comprises about 3% of adult cancer cases and is an aggressive tumor characterized in most cases by the inactivation of the tumor -suppressor gene VHL. The Von Hippel–Lindau protein (pVHL) regulates the hypoxia-inducible factor (HIF), and the loss of the pVHL function causes constitutive stabilization of HIF-1α and HIF-2α, resulting in the induction of HIF-transcriptional targets [2]. HIF activates genes, which encode proteins associated with angiogenesis and cell -cycle regulation
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