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Current Drug Targets

Author(s): Kerstin Junker*, Markus Eckstein, Michelangelo Fiorentino and Rodolfo Montironi

DOI: 10.2174/1389450121666200326123700

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PD1/PD-L1 Axis in Uro-oncology

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Abstract

The immune system is important to control tumor development and progression in humans. However, tumor cells and cells of the tumor microenvironment can induce immune escape mechanisms including activation of immune checkpoints such as PD-1/PD-L1. Based on this knowledge, new immune therapies, including PD-1 and PD-L1 inhibition, have been developed and are already recommended as a standard treatment in metastatic bladder and kidney cancer patients. In addition to its role as a therapeutic target, PD-L1 seems to be a prognostic parameter although data are controversial. Only little is known about signaling pathways inducing PD-L1 expression in tumor cells on one hand and about its functional role for tumor cells itself. However, the understanding of the complex biological function of PD-L1 will improve therapeutic options in urological malignancies. This review is giving an overview of the current knowledge concerning the PD-1/PD-L1 axis in urological tumors including bladder, kidney, prostate, testicular and penile cancer.

Keywords: Checkpoint inhibition, PD-L1, bladder cancer, prostate cancer, kidney cancer, testicular germ cell tumors, penile cancer.

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[1]
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12(4): 252-64.
[http://dx.doi.org/10.1038/nrc3239] [PMID: 22437870]
[2]
Ribas A, Hu-Lieskovan S. What does PD-L1 positive or negative mean? J Exp Med 2016; 213(13): 2835-40.
[http://dx.doi.org/10.1084/jem.20161462] [PMID: 27903604]
[3]
Pfannstiel C, Strissel PL, Chiappinelli KB, et al. The tumor immune microenvironment drives a prognostic relevance that correlates with bladder cancer subtypes. Cancer Immunol Res 2019; 7(6): 923-38.
[http://dx.doi.org/10.1158/2326-6066.CIR-18-0758] [PMID: 30988029]
[4]
Dong P, Xiong Y, Yue J, Hanley SJB, Watari H. Tumor-intrinsic pd-l1 signaling in cancer initiation, development and treatment: beyond immune evasion. Front Oncol 2018; 8(386): 386.
[http://dx.doi.org/10.3389/fonc.2018.00386] [PMID: 30283733]
[5]
Almozyan S, Colak D, Mansour F, et al. PD-L1 promotes OCT4 and Nanog expression in breast cancer stem cells by sustaining PI3K/AKT pathway activation. Int J Cancer 2017; 141(7): 1402-12.
[http://dx.doi.org/10.1002/ijc.30834] [PMID: 28614911]
[6]
Crane CA, Panner A, Murray JC, et al. PI(3) kinase is associated with a mechanism of immunoresistance in breast and prostate cancer. Oncogene 2009; 28(2): 306-12.
[http://dx.doi.org/10.1038/onc.2008.384] [PMID: 18850006]
[7]
Zhong F, Cheng X, Sun S, Zhou J. Transcriptional activation of PD-L1 by Sox2 contributes to the proliferation of hepatocellular carcinoma cells. Oncol Rep 2017; 37(5): 3061-7.
[http://dx.doi.org/10.3892/or.2017.5523] [PMID: 28339084]
[8]
Chen J, Jiang CC, Jin L, Zhang XD. Regulation of PD-L1: a novel role of pro-survival signalling in cancer. Ann Oncol 2016; 27(3): 409-16.
[http://dx.doi.org/10.1093/annonc/mdv615] [PMID: 26681673]
[9]
Kataoka K, Shiraishi Y, Takeda Y, et al. Aberrant PD-L1 expression through 3′-UTR disruption in multiple cancers. Nature 2016; 534(7607): 402-6.
[http://dx.doi.org/10.1038/nature18294] [PMID: 27281199]
[10]
Liu X-D, Hoang A, Zhou L, et al. Resistance to antiangiogenic therapy is associated with an immunosuppressive tumor microenvironment in metastatic renal cell carcinoma. Cancer Immunol Res 2015; 3(9): 1017-29.
[http://dx.doi.org/10.1158/2326-6066.CIR-14-0244] [PMID: 26014097]
[11]
Balar AV, Castellano D, O’Donnell PH, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol 2017; 18(11): 1483-92.
[http://dx.doi.org/10.1016/S1470-2045(17)30616-2] [PMID: 28967485]
[12]
Balar AV, Galsky MD, Rosenberg JE, et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet 2017; 389(10064): 67-76.
[http://dx.doi.org/10.1016/S0140-6736(16)32455-2] [PMID: 27939400]
[13]
Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 2016; 387(10031): 1909-20.
[http://dx.doi.org/10.1016/S0140-6736(16)00561-4] [PMID: 26952546]
[14]
Bellmunt J, Bajorin DF. Pembrolizumab for Advanced Urothelial Carcinoma. N Engl J Med 2017; 376(23): 2304.
[PMID: 28591526]
[15]
Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med 2017; 376(11): 1015-26.
[http://dx.doi.org/10.1056/NEJMoa1613683] [PMID: 28212060]
[16]
Plimack ER, Bellmunt J, Gupta S, et al. Safety and activity of pembrolizumab in patients with locally advanced or metastatic urothelial cancer (KEYNOTE-012): a non-randomised, open-label, phase 1b study. Lancet Oncol 2017; 18(2): 212-20.
[http://dx.doi.org/10.1016/S1470-2045(17)30007-4] [PMID: 28081914]
[17]
Patel MR, Ellerton J, Infante JR, et al. Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. Lancet Oncol 2018; 19(1): 51-64.
[http://dx.doi.org/10.1016/S1470-2045(17)30900-2] [PMID: 29217288]
[18]
Powles T, O’Donnell PH, Massard C, et al. Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: updated results from a phase 1/2 open-label study. JAMA Oncol 2017; 3(9) e172411.
[http://dx.doi.org/10.1001/jamaoncol.2017.2411] [PMID: 28817753]
[19]
Sharma P, Callahan MK, Bono P, et al. Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): a multicentre, open-label, two-stage, multi-arm, phase 1/2 trial. Lancet Oncol 2016; 17(11): 1590-8.
[http://dx.doi.org/10.1016/S1470-2045(16)30496-X] [PMID: 27733243]
[20]
Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol 2017; 18(3): 312-22.
[http://dx.doi.org/10.1016/S1470-2045(17)30065-7] [PMID: 28131785]
[21]
Keytruda (pembrolizumab) or Tecentriq (atezolizumab): FDA Alerts Health Care Professionals and Investigators: FDA Statement - Decreased Survival in Some Patients in Clinical Trials Associated with Monotherapy. 2018.
[22]
EMA restricts use of Keytruda and Tecentriq in bladder cancer Data show lower survival in some patients with low levels of cancer protein PD-L1 2018.
[23]
Gourd E. EMA restricts use of anti-PD-1 drugs for bladder cancer. The Lancet Oncology
[http://dx.doi.org/10.1016/S1470-2045(18)30433-9]
[24]
Schwamborn K, Ammann JU, Knüchel R, et al. Multicentric analytical comparability study of programmed death-ligand 1 expression on tumor-infiltrating immune cells and tumor cells in urothelial bladder cancer using four clinically developed immunohistochemistry assays. Virchows Arch 2019; 475(5): 599-608.
[http://dx.doi.org/10.1007/s00428-019-02610-z] [PMID: 31267201]
[25]
Eckstein M, Erben P, Kriegmair MC, et al. Performance of the Food and Drug Administration/EMA-approved programmed cell death ligand-1 assays in urothelial carcinoma with emphasis on therapy stratification for first-line use of atezolizumab and pembrolizumab. Eur J Cancer 2019; 106: 234-43.
[http://dx.doi.org/10.1016/j.ejca.2018.11.007] [PMID: 30528808]
[26]
Rijnders M, van der Veldt AAM, Zuiverloon TCM, et al. PD-L1 antibody comparison in urothelial carcinoma. Eur Urol 2019; 75(3): 538-40.
[http://dx.doi.org/10.1016/j.eururo.2018.11.002] [PMID: 30497882]
[27]
Zavalishina L, Tsimafeyeu I, Povilaitite P, et al. RUSSCO-RSP comparative study of immunohistochemistry diagnostic assays for PD-L1 expression in urothelial bladder cancer. Virchows Arch 2018; 473(6): 719-24.
[http://dx.doi.org/10.1007/s00428-018-2453-7] [PMID: 30209552]
[28]
Ionescu DN, Downes MR, Christofides A, Tsao MS. Harmonization of PD-L1 testing in oncology: a Canadian pathology perspective. Curr Oncol 2018; 25(3): e209-16.
[http://dx.doi.org/10.3747/co.25.4031] [PMID: 29962847]
[29]
Hodgson A, Slodkowska E, Jungbluth A, et al. Pd-l1 immunohistochemistry assay concordance in urothelial carcinoma of the bladder and hypopharyngeal squamous cell carcinoma. Am J Surg Pathol 2018; 42(8): 1059-66.
[http://dx.doi.org/10.1097/PAS.0000000000001084] [PMID: 29750666]
[30]
Tretiakova M, Fulton R, Kocherginsky M, et al. Concordance study of PD-L1 expression in primary and metastatic bladder carcinomas: comparison of four commonly used antibodies and RNA expression. Mod Pathol 2018; 31(4): 623-32.
[http://dx.doi.org/10.1038/modpathol.2017.188] [PMID: 29271413]
[31]
Schats KA, Van Vré EA, Boeckx C, et al. Optimal evaluation of programmed death ligand-1 on tumor cells versus immune cells requires different detection methods. Arch Pathol Lab Med 2018; 142(8): 982-91.
[http://dx.doi.org/10.5858/arpa.2017-0159-OA] [PMID: 29607663]
[32]
Schats KA, Van Vré EA, De Schepper S, et al. Validated programmed cell death ligand 1 immunohistochemistry assays (E1L3N and SP142) reveal similar immune cell staining patterns in melanoma when using the same sensitive detection system. Histopathology 2017; 70(2): 253-63.
[http://dx.doi.org/10.1111/his.13056] [PMID: 27496355]
[33]
Boorjian SA, Sheinin Y, Crispen PL, Farmer SA, Lohse CM, Kuntz SM, et al. T-cell coregulatory molecule expression in urothelial cell carcinoma: clinicopathologic correlations and association with survival. Clin Cancer Res 2008; 14(15): 4800-8.
[34]
Faraj SF, Munari E, Guner G, Taube J, Anders R, Hicks J, et al. Assessment of tumoral PD-L1 expression and intratumoral CD8+ T cells in urothelial carcinoma. Urology 2015; 85(3): 703 e1-6.
[35]
Inman BA, Sebo TJ, Frigola X, et al. PD-L1 (B7-H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata: associations with localized stage progression. Cancer 2007; 109(8): 1499-505.
[http://dx.doi.org/10.1002/cncr.22588] [PMID: 17340590]
[36]
Miyama Y, Miyakawa J, Morikawa T. Re: Prognostic Value of PD-1 and PD-L1 Expression in Patients with High Grade Upper Tract Urothelial Carcinoma: L.M. Krabbe, B. Heitplatz, S. Preuss, R.C. Hutchinson, S.L. Woldu, N. Singla, M. Boegemann, C.G. Wood, J.A. Karam, A.Z. Weizer, J.D. Raman, M. Remzi, N. Rioux-Leclercq, A. Haitel, L.M. Rapoport, P.V. Glybochko, M. Roscigno, C. Bolenz, K. Bensalah, A.I. Sagalowsky, S.F. Shariat, Y. Lotan, E. Xylinas and V. Margulis J Urol 2017;198:1253-1262. J Urol 2018; 199(5): 1353-4.
[http://dx.doi.org/10.1016/j.juro.2017.11.128] [PMID: 29428637]
[37]
Krabbe LM, Heitplatz B, Preuss S, et al. Prognostic Value of PD-1 and PD-L1 Expression in Patients with High Grade Upper Tract Urothelial Carcinoma. J Urol 2017; 198(6): 1253-62.
[http://dx.doi.org/10.1016/j.juro.2017.06.086] [PMID: 28668287]
[38]
Nakanishi J, Wada Y, Matsumoto K, Azuma M, Kikuchi K, Ueda S. Overexpression of B7-H1 (PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers. Cancer Immunol Immunother 2007; 56(8): 1173-82.
[http://dx.doi.org/10.1007/s00262-006-0266-z] [PMID: 17186290]
[39]
Wang Q, Liu F, Liu L. Prognostic significance of PD-L1 in solid tumor: An updated meta-analysis. Medicine (Baltimore) 2017; 96(18) e6369.
[http://dx.doi.org/10.1097/MD.0000000000006369] [PMID: 28471952]
[40]
Wu P, Wu D, Li L, Chai Y, Huang J. PD-L1 and Survival in Solid Tumors: A Meta-Analysis. PLoS One 2015; 10(6) e0131403.
[http://dx.doi.org/10.1371/journal.pone.0131403] [PMID: 26114883]
[41]
Xylinas E, Robinson BD, Kluth LA, et al. Association of T-cell co-regulatory protein expression with clinical outcomes following radical cystectomy for urothelial carcinoma of the bladder. Eur J Surg Oncol 2014; 40(1): 121-7.
[http://dx.doi.org/10.1016/j.ejso.2013.08.023] [PMID: 24140000]
[42]
Zhang B, Yu W, Feng X, et al. Prognostic significance of PD-L1 expression on tumor cells and tumor-infiltrating mononuclear cells in upper tract urothelial carcinoma. Med Oncol 2017; 34(5): 94.
[http://dx.doi.org/10.1007/s12032-017-0941-2] [PMID: 28409437]
[43]
Eckstein M, Wirtz RM, Pfannstil C, et al. A multicenter round robin test of PD-L1 expression assessment in urothelial bladder cancer by immunohistochemistry and RT-qPCR with emphasis on prognosis prediction after radical cystectomy. Oncotarget 2018; 9(19): 15001-14.
[http://dx.doi.org/10.18632/oncotarget.24531] [PMID: 29599921]
[44]
Breyer J, Wirtz RM, Otto W, et al. High PDL1 mRNA expression predicts better survival of stage pT1 non-muscle-invasive bladder cancer (NMIBC) patients. Cancer Immunol Immunother 2018; 67(3): 403-12.
[http://dx.doi.org/10.1007/s00262-017-2093-9] [PMID: 29150702]
[45]
Powles T, Durán I, van der Heijden MS, et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet 2018; 391(10122): 748-57.
[http://dx.doi.org/10.1016/S0140-6736(17)33297-X] [PMID: 29268948]
[46]
Powles T, Kockx M, Rodriguez-Vida A, et al. Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial. Nat Med 2019; 25(11): 1706-14.
[http://dx.doi.org/10.1038/s41591-019-0628-7] [PMID: 31686036]
[47]
Eckstein M, Gupta S. New insights in predictive determinants of the tumor immune microenvironment for immune checkpoint inhibition: a never ending story? Ann Transl Med 2019; 7(Suppl. 3): S135.
[http://dx.doi.org/10.21037/atm.2019.06.12] [PMID: 31576342]
[48]
Ott PA, Bang YJ, Piha-Paul SA, et al. T-cell-inflamed gene-expression profile, programmed death ligand 1 expression, and tumor mutational burden predict efficacy in patients treated with pembrolizumab across 20 cancers: KEYNOTE-028. J Clin Oncol 2019; 37(4): 318-27.
[http://dx.doi.org/10.1200/JCO.2018.78.2276] [PMID: 30557521]
[49]
Mariathasan S, Turley SJ, Nickles D, et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 2018; 554(7693): 544-8.
[http://dx.doi.org/10.1038/nature25501] [PMID: 29443960]
[50]
Wang L, Saci A, Szabo PM, et al. EMT- and stroma-related gene expression and resistance to PD-1 blockade in urothelial cancer. Nat Commun 2018; 9(1): 3503.
[http://dx.doi.org/10.1038/s41467-018-05992-x] [PMID: 30158554]
[51]
Wang Z, Peng S, Xie H, et al. Prognostic and clinicopathological significance of PD-L1 in patients with renal cell carcinoma: a meta-analysis based on 1863 individuals. Clin Exp Med 2018; 18(2): 165-75.
[http://dx.doi.org/10.1007/s10238-018-0488-3] [PMID: 29362922]
[52]
Zhu Q, Cai M-Y, Weng D-S, et al. PD-L1 expression patterns in tumour cells and their association with CD8+ tumour infiltrating lymphocytes in clear cell renal cell carcinoma. J Cancer 2019; 10(5): 1154-61.
[http://dx.doi.org/10.7150/jca.29052] [PMID: 30854124]
[53]
Giraldo NA, Becht E, Pagès F, et al. Orchestration and prognostic significance of immune checkpoints in the microenvironment of primary and metastatic renal cell cancer. Clin Cancer Res 2015; 21(13): 3031-40.
[http://dx.doi.org/10.1158/1078-0432.CCR-14-2926] [PMID: 25688160]
[54]
Shin S-J, Jeon YK, Kim P-J, et al. Clinicopathologic analysis of pd-l1 and pd-l2 expression in renal cell carcinoma: association with oncogenic proteins status. Ann Surg Oncol 2016; 23(2): 694-702.
[http://dx.doi.org/10.1245/s10434-015-4903-7] [PMID: 26464193]
[55]
Kammerer-Jacquet S-F, Crouzet L, Brunot A, 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(1): 142-8.
[http://dx.doi.org/10.1002/ijc.30429] [PMID: 27623354]
[56]
Mikami S, Mizuno R, Kondo T, et al. Clinical significance of programmed death-1 and programmed death-ligand 1 expression in the tumor microenvironment of clear cell renal cell carcinoma. Cancer Sci 2019; 110(6): 1820-8.
[http://dx.doi.org/10.1111/cas.14019] [PMID: 30972888]
[57]
Basu A, Yearley JH, Annamalai L, Pryzbycin C, Rini B. Association of pd-l1, pd-l2, and immune response markers in matched renal clear cell carcinoma primary and metastatic tissue specimens. Am J Clin Pathol 2019; 151(2): 217-25.
[http://dx.doi.org/10.1093/ajcp/aqy141] [PMID: 30346474]
[58]
Tatli Dogan H, Kiran M, Bilgin B, et al. 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. Diagn Pathol 2018; 13(1): 60.
[http://dx.doi.org/10.1186/s13000-018-0742-8] [PMID: 30144808]
[59]
Carlsson J, Sundqvist P, Kosuta V, Falt A, Giunchi F, Fiorentino M, et al. Pd-l1 expression is associated with poor prognosis in renal cell carcinoma. applied immunohistochemistry & molecular morphology : AIMM 2019.
[60]
Kahlmeyer A, Stöhr CG, Hartmann A, et al. Expression of PD-1 and CTLA-4 Are Negative Prognostic Markers in Renal Cell Carcinoma. J Clin Med 2019; 8(5): 743.
[http://dx.doi.org/10.3390/jcm8050743] [PMID: 31137694]
[61]
Zhang XM, Shen PF, Zeng H. Differential expressions of PD-1, PD-L1, and PD-L2 between the primary and metastatic sites in renal cell carcinoma. J Clin Oncol 2018; 36(6)
[http://dx.doi.org/10.1200/JCO.2018.36.6_suppl.616]
[62]
Erlmeier F, Weichert W, Schrader AJ, et al. Prognostic impact of PD-1 and its ligands in renal cell carcinoma. Med Oncol 2017; 34(6): 99.
[http://dx.doi.org/10.1007/s12032-017-0961-y] [PMID: 28432616]
[63]
Bersanelli M, Gnetti L, Varotti E, et al. Immune context characterization and heterogeneity in primary tumors and pulmonary metastases from renal cell carcinoma. Immunotherapy 2019; 11(1): 21-35.
[http://dx.doi.org/10.2217/imt-2018-0097] [PMID: 30702014]
[64]
Ueda K, Suekane S, Kurose H, Chikui K, Nakiri M, Nishihara K, et al. Prognostic value of PD-1 and PD-L1 expression in patients with metastatic clear cell renal cell carcinoma. Urologic Oncology: Seminars and Original Investigations 2018; 36(11): 499.e9-e16.
[65]
Motoshima T, Komohara Y, Ma C, et al. PD-L1 expression in papillary renal cell carcinoma. BMC Urol 2017; 17(1): 8.
[http://dx.doi.org/10.1186/s12894-016-0195-x] [PMID: 28086852]
[66]
Erlmeier F, Hartmann A, Autenrieth M, et al. PD-1/PD-L1 expression in chromophobe renal cell carcinoma: An immunological exception? Med Oncol 2016; 33(11): 120.
[http://dx.doi.org/10.1007/s12032-016-0833-x] [PMID: 27696122]
[67]
Abbas M, Steffens S, Bellut M, et al. Do programmed death 1 (PD-1) and its ligand (PD-L1) play a role in patients with non-clear cell renal cell carcinoma? Med Oncol 2016; 33(6): 59.
[http://dx.doi.org/10.1007/s12032-016-0770-8] [PMID: 27165272]
[68]
Kawakami F, Sircar K, Rodriguez-Canales J, et al. Programmed cell death ligand 1 and tumor-infiltrating lymphocyte status in patients with renal cell carcinoma and sarcomatoid dedifferentiation. Cancer 2017; 123(24): 4823-31.
[http://dx.doi.org/10.1002/cncr.30937] [PMID: 28832979]
[69]
Pichler R, Compérat E, Klatte T, et al. Renal Cell Carcinoma with Sarcomatoid Features: Finally New Therapeutic Hope? Cancers (Basel) 2019; 11(3) E422.
[http://dx.doi.org/10.3390/cancers11030422] [PMID: 30934624]
[70]
Guo C, Zhao H, Wang Y, et al. Prognostic value of the neo-immunoscore in renal cell carcinoma. Front Oncol 2019; 9: 439.
[http://dx.doi.org/10.3389/fonc.2019.00439] [PMID: 31192136]
[71]
Shuch B, Falbo R, Parisi F, et al. MET expression in primary and metastatic clear cell renal cell carcinoma: implications of correlative biomarker assessment to met pathway inhibitors. BioMed Res Int 2015. 2015192406.
[http://dx.doi.org/10.1155/2015/192406] [PMID: 26448928]
[72]
Lalani AA, Gray KP, Albiges L, et al. Differential expression of c-Met between primary and metastatic sites in clear-cell renal cell carcinoma and its association with PD-L1 expression. Oncotarget 2017; 8(61): 103428-36.
[http://dx.doi.org/10.18632/oncotarget.21952] [PMID: 29262573]
[73]
Wang Y, Wang H, Zhao Q, Xia Y, Hu X, Guo J. PD-L1 induces epithelial-to-mesenchymal transition via activating SREBP-1c in renal cell carcinoma. Med Oncol 2015; 32(8): 212.
[http://dx.doi.org/10.1007/s12032-015-0655-2] [PMID: 26141060]
[74]
Sun C, Mezzadra R, Schumacher TN. Regulation and Function of the PD-L1 Checkpoint. Immunity 2018; 48(3): 434-52.
[http://dx.doi.org/10.1016/j.immuni.2018.03.014] [PMID: 29562194]
[75]
Hirayama Y, Gi M, Yamano S, et al. Anti-PD-L1 treatment enhances antitumor effect of everolimus in a mouse model of renal cell carcinoma. Cancer Sci 2016; 107(12): 1736-44.
[http://dx.doi.org/10.1111/cas.13099] [PMID: 27712020]
[76]
Zhang C, Duan Y, Xia M, et al. TFEB mediates immune evasion and resistance to mTOR inhibition of renal cell carcinoma via induction of PD-L1. Clin Cancer Res 2019; 25(22): 6827-38.
[http://dx.doi.org/10.1158/1078-0432.CCR-19-0733] [PMID: 31383732]
[77]
Qu F, Ye J, Pan X, et al. MicroRNA-497-5p down-regulation increases PD-L1 expression in clear cell renal cell carcinoma. J Drug Target 2019; 27(1): 67-74.
[http://dx.doi.org/10.1080/1061186X.2018.1479755] [PMID: 30183478]
[78]
Cheng X, Dai H, Wan N, Moore Y, Vankayalapati R, Dai Z. Interaction of programmed death-1 and programmed death-1 ligand-1 contributes to testicular immune privilege. Transplantation 2009; 87(12): 1778-86.
[http://dx.doi.org/10.1097/TP.0b013e3181a75633] [PMID: 19543053]
[79]
Jennewein L, Bartsch G, Gust K, et al. Increased tumor vascularization is associated with the amount of immune competent PD-1 positive cells in testicular germ cell tumors. Oncol Lett 2018; 15(6): 9852-60.
[http://dx.doi.org/10.3892/ol.2018.8597] [PMID: 29928359]
[80]
Cierna Z, Mego M, Miskovska V, et al. Prognostic value of programmed-death-1 receptor (PD-1) and its ligand 1 (PD-L1) in testicular germ cell tumors. Ann Oncol 2016; 27(2): 300-5.
[http://dx.doi.org/10.1093/annonc/mdv574] [PMID: 26598537]
[81]
Fankhauser CD, Curioni-Fontecedro A, Allmann V, et al. Frequent PD-L1 expression in testicular germ cell tumors. Br J Cancer 2015; 113(3): 411-3.
[http://dx.doi.org/10.1038/bjc.2015.244] [PMID: 26171934]
[82]
Chovanec M, Cierna Z, Miskovska V, et al. Prognostic role of programmed-death ligand 1 (PD-L1) expressing tumor infiltrating lymphocytes in testicular germ cell tumors. Oncotarget 2017; 8(13): 21794-805.
[http://dx.doi.org/10.18632/oncotarget.15585] [PMID: 28423520]
[83]
Chovanec M, Cierna Z, Miskovska V, et al. Systemic immune-inflammation index in germ-cell tumours. Br J Cancer 2018; 118(6): 831-8.
[http://dx.doi.org/10.1038/bjc.2017.460] [PMID: 29485980]
[84]
Djajadiningrat RS, Jordanova ES, Kroon BK, et al. Human papillomavirus prevalence in invasive penile cancer and association with clinical outcome. J Urol 2015; 193(2): 526-31.
[http://dx.doi.org/10.1016/j.juro.2014.08.087] [PMID: 25150641]
[85]
Ferrándiz-Pulido C, Masferrer E, de Torres I, et al. Identification and genotyping of human papillomavirus in a Spanish cohort of penile squamous cell carcinomas: correlation with pathologic subtypes, p16(INK4a) expression, and prognosis. J Am Acad Dermatol 2013; 68(1): 73-82.
[http://dx.doi.org/10.1016/j.jaad.2012.05.029] [PMID: 22863066]
[86]
Ottenhof SR, Djajadiningrat RS, Thygesen HH, et al. The prognostic value of immune factors in the tumor microenvironment of penile squamous cell carcinoma. Front Immunol 2018; 9(1253): 1253.
[http://dx.doi.org/10.3389/fimmu.2018.01253] [PMID: 29942303]
[87]
Udager AM, Liu TY, Skala SL, et al. Frequent PD-L1 expression in primary and metastatic penile squamous cell carcinoma: potential opportunities for immunotherapeutic approaches. Ann Oncol 2016; 27(9): 1706-12.
[http://dx.doi.org/10.1093/annonc/mdw216] [PMID: 27217541]
[88]
Ottenhof SR, Djajadiningrat RS, de Jong J, Thygesen HH, Horenblas S, Jordanova ES. Expression of programmed death ligand 1 in penile cancer is of prognostic value and associated with hpv status. J Urol 2017; 197(3 Pt 1): 690-7.
[http://dx.doi.org/10.1016/j.juro.2016.09.088] [PMID: 27697578]
[89]
Deng C, Li Z, Guo S, Chen P, Chen X, Zhou Q, et al. Tumor PD-L1 expression is correlated with increased TILs and poor prognosis in penile squamous cell carcinoma. Oncoimmunology 2016; 6(2) e1269047.
[90]
Davidsson S, Carlsson J, Giunchi F, et al. PD-L1 Expression in Men with Penile Cancer and its Association with Clinical Outcomes. Eur Urol Oncol 2019; 2(2): 214-21.
[http://dx.doi.org/10.1016/j.euo.2018.07.010] [PMID: 31017099]
[91]
De Velasco MA, Uemura H. Prostate cancer immunotherapy: where are we and where are we going? Curr Opin Urol 2018; 28(1): 15-24.
[http://dx.doi.org/10.1097/MOU.0000000000000462] [PMID: 29095729]
[92]
Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010; 363(5): 411-22.
[http://dx.doi.org/10.1056/NEJMoa1001294] [PMID: 20818862]
[93]
Beer TM, Kwon ED, Drake CG, et al. Randomized, double-blind, phase iii trial of ipilimumab versus placebo in asymptomatic or minimally symptomatic patients with metastatic chemotherapy-naive castration-resistant prostate cancer. J Clin Oncol 2017; 35(1): 40-7.
[http://dx.doi.org/10.1200/JCO.2016.69.1584] [PMID: 28034081]
[94]
Rodrigues DN, Rescigno P, Liu D, et al. Immunogenomic analyses associate immunological alterations with mismatch repair defects in prostate cancer. J Clin Invest 2018; 128(11): 5185.
[http://dx.doi.org/10.1172/JCI125184] [PMID: 30382943]
[95]
Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017; 357(6349): 409-13.
[http://dx.doi.org/10.1126/science.aan6733] [PMID: 28596308]
[96]
Antonarakis ES, Piulats JM, Gross-Goupil M, Goh J, Ojamaa K, Hoimes CJ, et al. Pembrolizumab for treatment-refractory metastatic castration-resistant prostate cancer: multicohort, open-label phase ii keynote-199 study. J Clin Oncol 2019. JCO1901638.
[PMID: 31774688]
[97]
Li Y, Huang Q, Zhou Y, et al. The Clinicopathologic and prognostic significance of programmed cell death ligand 1 (pd-l1) expression in patients with prostate cancer: a systematic review and meta-analysis. Front Pharmacol 2019; 9: 1494.
[http://dx.doi.org/10.3389/fphar.2018.01494] [PMID: 30733677]
[98]
Zhao SG, Lehrer J, Chang SL, et al. The immune landscape of prostate cancer and nomination of pd-l2 as a potential therapeutic target. J Natl Cancer Inst 2019; 111(3): 301-10.
[http://dx.doi.org/10.1093/jnci/djy141] [PMID: 30321406]
[99]
Cimadamore A, Lopez-Beltran A, Massari F, Santoni M, Mazzucchelli R, Scarpelli M, et al. Germline and somatic mutations in prostate cancer: focus on defective DNA repair, PARP inhibitors and immunotherapy. Future Oncol 0(0): null.