Top

Published in:

01-05-2018 | Original Article

Prognostic and clinicopathological significance of PD-L1 in patients with renal cell carcinoma: a meta-analysis based on 1863 individuals

Authors: Zhun Wang, Shuanghe Peng, Hui Xie, Linpei Guo, Qiliang Cai, Zhiqun Shang, Ning Jiang, Yuanjie Niu

Published in: Clinical and Experimental Medicine | Issue 2/2018

Abstract

The prognostic significance of PD-L1 in renal cell carcinoma (RCC) had been investigated in previous studies; however, the results remain controversial. The primary aim of this meta-analysis was to investigate the prognostic and clinicopathological significance of the PD-L1 expression in patients with RCC. Relevant literature was identified form PubMed, Embase, Web of Science and Cochrane library, which compared the prognostic significance between PD-L1 expression and RCC. Hazard ratios (HRs) for survival outcomes and odds ratios (ORs) for clinical parameters associated with PD-L1 were extracted from eligible studies. Heterogeneity was assessed using the I² value. The fixed-effects model was used if there was no evidence of heterogeneity; otherwise, the random-effects model was used. Publication bias was evaluated using Begg’s funnel plots and Egger’s regression test. A total of 1863 patients from ten eligible studies were analyzed. The results showed that PD-L1 expression is associated with poor overall survival in clear cell RCC (ccRCC) (HR = 2.76, 95%CI: 2.25–3.38, I² = 14.4%, P < 0.001) and non-clear cell RCC (non-ccRCC) (HR = 2.77, 95%CI: 1.62–4.72, I² = 28.8%, P < 0.001). In addition, PD-L1 expression was found to be significantly associated with primary tumor stage (OR = 1.76, 95%CI: 1.39–2.23; I² = 56.3%), regional lymph node involvement (OR = 2.10, 95%CI: 1.48–2.98; I² = 14.9%), distant metastases (OR = 2.69, 95%CI: 2.05–3.54; I² = 0.0%), nuclear grade (OR = 1.72, 95%CI: 1.32–2.23; I² = 79.4%) and histologic tumor necrosis (OR = 2.25, 95%CI: 1.59–3.18; I² = 66.1%) in patients with RCC. The outcome stability was confirmed by sensitivity analysis. Both the Begg’s funnel plot test (P = 0.276) and the Egger’s (P = 0.388) verified that there was no publication bias within the included studies. This study suggests that PD-L1 expression is correlated with poor prognosis and advanced clinicopathological features in RCC patients.

Rini BI, Campbell SC, Escudier B. Renal cell carcinoma. Lancet. 2009;373(9669):1119–32. https://doi.org/10.1016/s0140-6736(09)60229-4.CrossRefPubMed

Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108. https://doi.org/10.3322/caac.21262.CrossRefPubMed

Fitzmaurice C, Dicker D, Pain A, Hamavid H, Moradi-Lakeh M, MacIntyre MF, et al. The global burden of cancer 2013. JAMA Oncol. 2015;1(4):505–27. https://doi.org/10.1001/jamaoncol.2015.0735.CrossRefPubMed

Escudier B, Porta C, Schmidinger M, Algaba F, Patard JJ, Khoo V, et al. Renal cell carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up†. Ann Oncol. 2014;25(suppl_3):iii49–56. https://doi.org/10.1093/annonc/mdu259.CrossRefPubMed

Iacovelli R, Sternberg CN, Porta C, Verzoni E, de Braud F, Escudier B, et al. Inhibition of the VEGF/VEGFR pathway improves survival in advanced kidney cancer: a systematic review and meta-analysis. Curr Drug Targets. 2015;16(2):164–70.CrossRefPubMed

Heng DY, Xie W, Regan MM, Warren MA, Golshayan AR, Sahi C, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol Off J Am Soc Clin Oncol. 2009;27(34):5794–9. https://doi.org/10.1200/jco.2008.21.4809.CrossRef

Motzer R, Escudier B, McDermott D, George S, Hammers H, Srinivas S, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803–13.CrossRefPubMedPubMedCentral

Postow MA, Callahan MK, Wolchok JD. Immune checkpoint blockade in cancer therapy. J Clin Oncol Off J Am Soc Clin Oncol. 2015;33(17):1974–82. https://doi.org/10.1200/jco.2014.59.4358.CrossRef

Afreen S, Dermime S. The immunoinhibitory B7-H1 molecule as a potential target in cancer: killing many birds with one stone. Hematol Oncol Stem Cell Therapy. 2014;7(1):1–17. https://doi.org/10.1016/j.hemonc.2013.09.005.CrossRef

10.

Fusi A, Festino L, Botti G, Masucci G, Melero I, Lorigan P, et al. PD-L1 expression as a potential predictive biomarker. Lancet Oncol. 2015;16(13):1285–7. https://doi.org/10.1016/s1470-2045(15)00307-1.CrossRefPubMed

11.

Berghoff AS, Kiesel B, Widhalm G, Rajky O, Ricken G, Wohrer A, et al. Programmed death ligand 1 expression and tumor-infiltrating lymphocytes in glioblastoma. Neuro-Oncology. 2015;17(8):1064–75. https://doi.org/10.1093/neuonc/nou307.CrossRefPubMed

12.

Zhao LW, Li C, Zhang RL, Xue HG, Zhang FX, Zhang F, et al. B7-H1 and B7-H4 expression in colorectal carcinoma: correlation with tumor FOXP3⁺ regulatory T-cell infiltration. Acta Histochem. 2014;116(7):1163–8. https://doi.org/10.1016/j.acthis.2014.06.003.CrossRefPubMed

13.

Wang YH, Cao YW, Yang XC, Niu HT, Sun LJ, Wang XS, et al. Effect of TLR4 and B7-H1 on immune escape of urothelial bladder cancer and its clinical significance. Asian Pac J Cancer Prev. 2014;15(3):1321–6. https://doi.org/10.7314/apjcp.2014.15.3.1321.CrossRefPubMed

14.

Muenst S, Schaerli AR, Gao F, Däster S, Trella E, Droeser RA, et al. Expression of programmed death ligand 1 (PD-L1) is associated with poor prognosis in human breast cancer. Breast Cancer Res Treat. 2014;146(1):15–24. https://doi.org/10.1007/s10549-014-2988-5.CrossRefPubMed

15.

Jiang D, Xu Y, Li F, Xu B, Zhang X. The role of B7-H1 in gastric carcinoma: clinical significance and related mechanism. Med Oncol (Northwood, Lond, Engl). 2014;31(11):268. https://doi.org/10.1007/s12032-014-0268-1.CrossRef

16.

Tamura H, Ishibashi M, Yamashita T, Tanosaki S, Okuyama N, Kondo A, et al. Marrow stromal cells induce B7-H1 expression on myeloma cells, generating aggressive characteristics in multiple myeloma. Leukemia. 2013;27(2):464–72. https://doi.org/10.1038/leu.2012.213.CrossRefPubMed

17.

Boland JM, Kwon ED, Harrington SM, Wampfler JA, Tang H, Yang P, et al. Tumor B7-H1 and B7-H3 expression in squamous cell carcinoma of the lung. Clin Lung Cancer. 2013;14(2):157–63. https://doi.org/10.1016/j.cllc.2012.05.006.CrossRefPubMed

18.

Bigelow E, Bever KM, Xu H. Immunohistochemical staining of B7-H1 (PD-L1) on paraffin-embedded slides of pancreatic adenocarcinoma tissue. J Vis Exp. 2013;2013(71):4059.

19.

Chen J, Li G, Meng H, Fan Y, Song Y, Wang S, et al. Upregulation of B7-H1 expression is associated with macrophage infiltration in hepatocellular carcinomas. Cancer Immunol Immunother. 2012;61(1):101–8. https://doi.org/10.1007/s00262-011-1094-3.CrossRefPubMed

20.

Karim R, Jordanova ES, Piersma SJ, Kenter GG, Chen L, Boer JM, et al. Tumor-expressed B7-H1 and B7-DC in relation to PD-1+ T-cell infiltration and survival of patients with cervical carcinoma. Clin Cancer Res. 2009;15(20):6341–7. https://doi.org/10.1158/1078-0432.ccr-09-1652.CrossRefPubMed

21.

Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int J Surg (Lond, Engl). 2010;8(5):336–41. https://doi.org/10.1016/j.ijsu.2010.02.007.CrossRef

22.

Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med. 2009;6(7):e1000100. https://doi.org/10.1371/journal.pmed.1000100.CrossRefPubMed

23.

Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010;25(9):603–5. https://doi.org/10.1007/s10654-010-9491-z.CrossRefPubMed

24.

Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials. 2007;8:16. https://doi.org/10.1186/1745-6215-8-16.CrossRefPubMed

25.

Handoll HH. Systematic reviews on rehabilitation interventions. Arch Phys Med Rehabil. 2006;87(6):875. https://doi.org/10.1016/j.apmr.2006.04.006.CrossRefPubMed

26.

Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–60. https://doi.org/10.1136/bmj.327.7414.557.CrossRefPubMed

27.

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 USA. 2004;101(49):17174–9. https://doi.org/10.1073/pnas.0406351101.CrossRefPubMed

28.

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. Can Res. 2006;66(7):3381–5. https://doi.org/10.1158/0008-5472.can-05-4303.CrossRef

29.

Krambeck AE, Dong H, Thompson RH, Kuntz SM, Lohse CM, Leibovich BC, et al. Survivin and B7-H1 are collaborative predictors of survival and represent potential therapeutic targets for patients with renal cell carcinoma. Clin Cancer Res Off J Am Assoc Cancer Res. 2007;13(6):1749–56. https://doi.org/10.1158/1078-0432.ccr-06-2129.CrossRef

30.

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 Off J Eur Soc Med Oncol. 2014;25(11):2178–84. https://doi.org/10.1093/annonc/mdu445.CrossRef

31.

Leite KR, Reis ST, Junior JP, Zerati M, Gomes Dde O, Camara-Lopes LH, et al. PD-L1 expression in renal cell carcinoma clear cell type is related to unfavorable prognosis. Diagn Pathol. 2015;10:189. https://doi.org/10.1186/s13000-015-0414-x.CrossRefPubMed

32.

Abbas M, Steffens S, Bellut M, Becker JU, Grosshennig A, Eggers H, 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 (Northwood, Lond, Engl). 2016;33(6):59. https://doi.org/10.1007/s12032-016-0770-8.CrossRef

33.

Abbas M, Steffens S, Bellut M, Eggers H, Grosshennig A, Becker JU, et al. Intratumoral expression of programmed death ligand 1 (PD-L1) in patients with clear cell renal cell carcinoma (ccRCC). Med Oncol. 2016;33(7):1–7. https://doi.org/10.1007/s12032-016-0794-0.CrossRef

34.

Shin SJ, Jeon YK, Kim PJ, Cho YM, Koh J, Chung DH, 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. https://doi.org/10.1245/s10434-015-4903-7.CrossRefPubMed

35.

Kammerer-Jacquet S-F, Crouzet L, Brunot A, Dagher J, Pladys A, Edeline J, 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. https://doi.org/10.1002/ijc.30429.CrossRefPubMed

36.

Motoshima T, Komohara Y, Ma C, Dewi AK, Noguchi H, Yamada S, et al. PD-L1 expression in papillary renal cell carcinoma. BMC Urol. 2017;17(1):8. https://doi.org/10.1186/s12894-016-0195-x.CrossRefPubMed

37.

Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med. 1999;5(12):1365–9.CrossRefPubMed

38.

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(8):793–800. https://doi.org/10.1038/nm730.CrossRefPubMed

39.

Blank C, Brown I, Peterson AC, Spiotto M, Iwai Y, Honjo T, et al. PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer Res. 2004;64(3):1140–5. https://doi.org/10.1158/0008-5472.can-03-3259.CrossRefPubMed

40.

Wintterle S, Schreiner B, Mitsdoerffer M, Schneider D, Chen L, Meyermann R, et al. Expression of the B7-related molecule B7-H1 by glioma cells. Potential Mech Immune Paralysis. 2003;63(21):7462–7.

41.

Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci USA. 2002;99(19):12293–7. https://doi.org/10.1073/pnas.192461099.CrossRefPubMed

42.

Ning XH, Gong YQ, He SM, Li T, Wang JY, Peng SH, et al. 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(2):3355–63. https://doi.org/10.18632/oncotarget.13765.CrossRefPubMed

43.

Iacovelli R, Nole F, Verri E, Renne G, Paglino C, Santoni M, et al. Prognostic role of PD-L1 expression in renal cell carcinoma. a systematic review and meta-analysis. Target Oncol. 2016;11(2):143–8. https://doi.org/10.1007/s11523-015-0392-7.CrossRefPubMed

44.

Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med. 1999;5(12):1365–9. https://doi.org/10.1038/70932.CrossRefPubMed

45.

Mazanet MM, Hughes CC. B7-H1 is expressed by human endothelial cells and suppresses T cell cytokine synthesis. J Immunol (Baltim, MD: 1950). 2002;169(7):3581–8.CrossRef

46.

Ishida M, Iwai Y, Tanaka Y, Okazaki T, Freeman GJ, Minato N, et al. Differential expression of PD-L1 and PD-L2, ligands for an inhibitory receptor PD-1, in the cells of lymphohematopoietic tissues. Immunol Lett. 2002;84(1):57–62.CrossRefPubMed

47.

Agata Y, Kawasaki A, Nishimura H, Ishida Y, Tsubata T, Yagita H, et al. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol. 1996;8(5):765–72.CrossRefPubMed

48.

Taube JM, Klein A, Brahmer JR, Xu H, Pan X, Kim JH, et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res Off J Am Assoc Cancer Res. 2014;20(19):5064–74. https://doi.org/10.1158/1078-0432.ccr-13-3271.CrossRef

49.

Sunshine J, Taube JM. PD-1/PD-L1 inhibitors. Curr Opin Pharmacol. 2015;23:32–8. https://doi.org/10.1016/j.coph.2015.05.011.CrossRefPubMed

50.

Kazandjian D, Suzman DL, Blumenthal G, Mushti S, He K, Libeg M, et al. FDA approval summary: nivolumab for the treatment of metastatic non-small cell lung cancer with progression on or after platinum-based chemotherapy. Oncologist. 2016;21(5):634–42. https://doi.org/10.1634/theoncologist.2015-0507.CrossRefPubMed

51.

Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–64. https://doi.org/10.1038/nrc3239.CrossRefPubMed

52.

Ornstein MC, Rini BI. The safety and efficacy of nivolumab for the treatment of advanced renal cell carcinoma. Expert Rev Anticancer Ther. 2016;16(6):577–84. https://doi.org/10.1080/14737140.2016.1184980.CrossRefPubMed

53.

Farolfi A, Schepisi G, Conteduca V, Burgio SL, Lolli C, De Giorgi U. Pharmacokinetics, pharmacodynamics and clinical efficacy of nivolumab in the treatment of metastatic renal cell carcinoma. Expert Opin Drug Metab Toxicol. 2016;12(9):1089–96. https://doi.org/10.1080/17425255.2016.1214713.CrossRefPubMed

54.

Albiges L, Fay AP, Xie W, Krajewski K, McDermott DF, Heng DY, et al. Efficacy of targeted therapies after PD-1/PD-L1 blockade in metastatic renal cell carcinoma. Eur J Cancer (Oxf, Engl: 1990). 2015;51(17):2580–6. https://doi.org/10.1016/j.ejca.2015.08.017.CrossRef

55.

Callea M, Albiges L, Gupta M, Cheng SC, Genega EM, Fay AP, et al. Differential expression of PD-L1 between primary and metastatic sites in clear-cell renal cell carcinoma. Cancer Immunol Res. 2015;3(10):1158–64. https://doi.org/10.1158/2326-6066.cir-15-0043.CrossRefPubMed

56.

Sutton AJ, Song F, Gilbody SM, Abrams KR. Modelling publication bias in meta-analysis: a review. Stat Methods Med Res. 2000;9(5):421–45. https://doi.org/10.1177/096228020000900503.CrossRefPubMed

Title: Prognostic and clinicopathological significance of PD-L1 in patients with renal cell carcinoma: a meta-analysis based on 1863 individuals
Authors: Zhun Wang
Shuanghe Peng
Hui Xie
Linpei Guo
Qiliang Cai
Zhiqun Shang
Ning Jiang
Yuanjie Niu
Publication date: 01-05-2018
Publisher: Springer International Publishing
Published in: Clinical and Experimental Medicine / Issue 2/2018
Print ISSN: 1591-8890
Electronic ISSN: 1591-9528
DOI: https://doi.org/10.1007/s10238-018-0488-3

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits

Illustration of figure on mountain summit/© Orapun / Stock.adobe.com, STEP AAG HeroTeaserCollection image/© Tarek / Generated with AI / Stock.adobe.com, ACC 2024 Pediatric and Congenital Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Pulmonary Vascular Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Valvular Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 HF and Cardiomyopathies: Year in Review/© 2024 American College of Cardiology, Woman out walking/© Seventyfour / stock.adobe.com (symbolic image with model), Woman checking smartwatch /© saltdium / stock.adobe.com (symbolic image with model), Cardiac catheterization/© Damian / stock.adobe.com

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2018

Xanthine oxidase and uric acid as independent predictors of albuminuria in patients with diabetes mellitus type 2

Kallikrein-related peptidase 6 (KLK6) expression differentiates tumor subtypes and predicts clinical outcome in breast cancer patients

Clinical trial design and recommendations: collectively, we can take them

Cytoplasmic expression of Twist1, an EMT-related transcription factor, is associated with higher grades renal cell carcinomas and worse progression-free survival in clear cell renal cell carcinoma

Clinical significance of circulating tumor cells from lung cancer patients using microfluidic chip

High mTOR expression independently prognosticates poor clinical outcome to induction chemotherapy in acute lymphoblastic leukemia

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

Highlights from the ACC 2024 Congress

ACC 2024 Congress Coverage