Abstract
Background
Immune checkpoint blockade therapy targeting programmed death (PD)-1 or PD-ligand1 (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 PD-L2 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.
Similar content being viewed by others
References
Fisher RI, Rosenberg SA, Fyfe G. Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell carcinoma. Cancer J Sci Am. 2000;6 Suppl 1:S55–7.
McDermott DF, Regan MM, Clark JI, Flaherty LE, Weiss GR, Logan TF, et al. Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol. 2005;23:133–41.
Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010;28:1061–8.
Rini BI, Campbell SC, Escudier B. Renal cell carcinoma. Lancet. 2009;373:1119–32.
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252–64.
Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455–65.
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–54.
Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8:793–800.
Tykodi SS. PD-1 as an emerging therapeutic target in renal cell carcinoma: current evidence. Onco Targets Ther. 2014;7:1349–59.
Sanmamed MF, Chen L. Inducible expression of B7-H1 (PD-L1) and its selective role in tumor site immune modulation. Cancer J. 2014;20:256–61.
Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol. 2012;24:207–12.
Thompson RH, Dong H, Kwon ED. Implications of B7-H1 expression in clear cell carcinoma of the kidney for prognostication and therapy. Clin Cancer Res. 2007;13:709s–15s.
Thompson RH, Kuntz SM, Leibovich BC, Dong H, Lohse CM, Webster WS, et al. Tumor B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term follow-up. Cancer Res. 2006;66:3381–5.
Choueiri TK, Fay AP, Gray KP, Callea M, Ho TH, Albiges L, et al. PD-L1 expression in nonclear-cell renal cell carcinoma. Ann Oncol. 2014;25:2178–84.
Ghiotto M, Gauthier L, Serriari N, Pastor S, Truneh A, Nunès J, et al. PD-L1 and PD-L2 differ in their molecular mechanisms of interaction with PD-1. Int Immunol. 2010;22:651–60.
Akbay EA, Koyama S, Carretero J, Altabef A, Tchaicha JH, Christensen C, et al. Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. Cancer Discov. 2013;3:1355–63.
Parsa AT, Waldron JS, Panner A, Crane CA, Parney IF, Barry JJ, et al. Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med. 2007;13:84–8.
Marzec M, Zhang Q, Goradia A, Raghunath PN, Liu X, Paessler M, et al. Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1). Proc Natl Acad Sci U S A. 2008;105:20852–7.
The International Agency for Research on Cancer. Pathology and genetics of tumours of the urinary system and male genital organs (IARC WHO classification of tumours). Lyon: IARC Press, 2004.
Delahunt B. Advances and controversies in grading and staging of renal cell carcinoma. Mod Pathol. 2009;22 Suppl 2:S24–36.
Thompson RH, Gillett MD, Cheville JC, Lohse CM, Dong H, Webster WS, 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.
Choueiri TK, Figueroa DJ, Fay AP, Signoretti S, Liu Y, Gagnon R, 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.
Thompson RH, Gillett MD, Cheville JC, Lohse CM, Dong H, Webster WS, et al. Costimulatory molecule B7-H1 in primary and metastatic clear cell renal cell carcinoma. Cancer. 2005;104:2084–91.
Ohigashi Y, Sho M, Yamada Y, Tsurui Y, Hamada K, Ikeda N, et al. Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer. Clin Cancer Res. 2005;11:2947–53.
Radhakrishnan S, Nguyen LT, Ciric B, Flies D, Van Keulen VP, Tamada K, et al. Immunotherapeutic potential of B7-DC (PD-L2) cross-linking antibody in conferring antitumor immunity. Cancer Res. 2004;64:4965–72.
Rozali EN, Hato SV, Robinson BW, Lake RA, Lesterhuis WJ. Programmed death ligand 2 in cancer-induced immune suppression. Clin Dev Immunol. 2012;2012:656340.
Hobo W, Maas F, Adisty N, de Witte T, Schaap N, van der Voort R, et al. siRNA silencing of PD-L1 and PD-L2 on dendritic cells augments expansion and function of minor histocompatibility antigen-specific CD8+ T cells. Blood. 2010;116:4501–11.
Jiang X, Zhou J, Giobbie-Hurder A, Wargo J, Hodi FS. The activation of MAPK in melanoma cells resistant to BRAF inhibition promotes PD-L1 expression that is reversible by MEK and PI3 K inhibition. Clin Cancer Res. 2013;19:598–609.
Noman MZ, Desantis G, Janji B, Hasmim M, Karray S, Dessen P, et al. PD-L1 is a novel direct target of HIF-1alpha, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med. 2014;211:781–90.
Barsoum IB, Smallwood CA, Siemens DR, Graham CH. A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells. Cancer Res. 2014;74:665–74.
Disclosure
No potential conflicts of interest were disclosed.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Shin, SJ., Jeon, Y.K., Kim, PJ. et al. Clinicopathologic Analysis of PD-L1 and PD-L2 Expression in Renal Cell Carcinoma: Association with Oncogenic Proteins Status. Ann Surg Oncol 23, 694–702 (2016). https://doi.org/10.1245/s10434-015-4903-7
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1245/s10434-015-4903-7