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. 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.
Surgical 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.
PD-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.
PD-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.
Messai Y, Gad S, Noman MZ, Le Teuff G, Couve S, Janji B, Kammerer SF, Rioux-Leclerc N, Hasmim M, Ferlicot S, et al. Renal cell carcinoma programmed death-ligand 1, a new direct target of hypoxia-inducible Factor-2 alpha, is regulated by von Hippel-Lindau gene mutation status. Eur Urol. 2016;70:623–32. CrossRefPubMed
Frigola X, Inman BA, Lohse CM, Krco CJ, Cheville JC, Thompson RH, Leibovich B, Blute ML, Dong H, Kwon ED. Identification of a soluble form of B7-H1 that retains immunosuppressive activity and is associated with aggressive renal cell carcinoma. Clin Cancer Res. 2011;17:1915–23. CrossRefPubMedPubMedCentral
Kammerer-Jacquet SF, Crouzet L, Brunot A, Dagher J, Pladys A, Edeline J, Laguerre B, Peyronnet B, Mathieu R, Verhoest G, et al. Independent association of PD-L1 expression with noninactivated VHL clear cell renal cell carcinoma-a finding with therapeutic potential. Int J Cancer. 2017;140:142–8. CrossRefPubMed
Biswas S, Charlesworth PJ, Turner GD, Leek R, Thamboo PT, Campo L, Turley H, Dildey P, Protheroe A, Cranston D, et al. CD31 angiogenesis and combined expression of HIF-1alpha and HIF-2alpha are prognostic in primary clear-cell renal cell carcinoma (CC-RCC), but HIFalpha transcriptional products are not: implications for antiangiogenic trials and HIFalpha biomarker studies in primary CC-RCC. Carcinogenesis. 2012;33:1717–25. CrossRefPubMed
Fan Y, Li H, Ma X, Gao Y, Chen L, Li X, Bao X, Du Q, Zhang Y, Zhang X. Prognostic significance of hypoxia-inducible factor expression in renal cell carcinoma: a PRISMA-compliant systematic review and meta-analysis. Medicine (Baltimore). 2015;94:e1646. CrossRef
WHO. Classification of Tumours of the Urinary System and Male Genital Organs. 4th edn. Lyon: IARC; 2016.
Miyazaki T, Ishikawa E, Matsuda M, Akutsu H, Osuka S, Sakamoto N, Takano S, Yamamoto T, Tsuboi K, Matsumura A. Assessment of PD-1 positive cells on initial and secondary resected tumor specimens of newly diagnosed glioblastoma and its implications on patient outcome. J Neuro-Oncol. 2017;133:277–85. CrossRef
Choueiri TK, Figueroa DJ, Fay AP, Signoretti S, Liu Y, Gagnon R, Deen K, Carpenter C, Benson P, Ho TH, et al. Correlation of PD-L1 tumor expression and treatment outcomes in patients with renal cell carcinoma receiving sunitinib or pazopanib: results from COMPARZ, a randomized controlled trial. Clin Cancer Res. 2015;21:1071–7. CrossRefPubMed
Ning XH, Gong YQ, He SM, Li T, Wang JY, Peng SH, Chen JC, Liu JY, Qi NN, Guo YL, Gong K. Higher programmed cell death 1 ligand 1 (PD-L1) mRNA level in clear cell renal cell carcinomas is associated with a favorable outcome due to the active immune responses in tumor tissues. Oncotarget. 2017;8:3355–63. PubMed
Thompson RH, Gillett MD, Cheville JC, Lohse CM, Dong H, Webster WS, Krejci KG, Lobo JR, Sengupta S, Chen L, et al. Costimulatory B7-H1 in renal cell carcinoma patients: Indicator of tumor aggressiveness and potential therapeutic target. Proc Natl Acad Sci U S A. 2004;101:17174–9. CrossRefPubMedPubMedCentral
- Prognostic significance of the programmed death ligand 1 expression in clear cell renal cell carcinoma and correlation with the tumor microenvironment and hypoxia-inducible factor expression
Hayriye Tatli Dogan
Mehmet Ali Nahit Sendur
Ali Fuat Atmaca
- BioMed Central