The clinicopathological and prognostic value of programmed death-ligand 1 in colorectal cancer: a meta-analysis
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Programmed death-ligand 1 (PD-L1) is reportedly expressed in colorectal tumors. However, the prognostic role of PD-L1 in colorectal cancer (CRC) remains controversial. Therefore, we performed a meta-analysis to investigate the clinicopathological and prognostic impact of PD-L1 in CRC.
A comprehensive search in PubMed, Embase, the Cochrane Library, Web of Science and the ClinicalTrials.gov for publications about PD-L1 expression in colorectal cancer was done. The correlation between PD-L1 expression and clinicopathological features or survival outcomes was analyzed by odds ratios (OR) or hazard ratios (HR), at 95% confidence intervals (CI).
The results show that the pooled HR of (1.34, 95% CI 1.02–1.65, p = 0.01) indicated the association of PD-L1 expression with overall survival (OS) in CRC patients. Meanwhile, the expression of PD-L1 was positively correlated with the lymph node metastasis (OR: 0.70, 95% CI 0.51–0.95, p = 0.00), gender (OR: 0.86, 95% CI 0.76–0.98, p = 0.05) and tumor location (OR: 1.39, 95% CI 1.14–1.71, p = 0.12).
These results suggest that high expression of PD-L1 is associated with low OS in CRC. High PD-L1 expression may act as a negative factor for patients with CRC and help to identify patients suitable for anticancer therapy.
KeywordsProgrammed death-ligand 1 Colorectal cancer Prognosis Meta-analysis
XN and JS: designed the study. XN, XS and LW: searched databases and collected full-text papers. YC, YZ and WL: performed statistical analysis. XN and DW: wrote the manuscript. All authors reviewed the final version of the manuscript.
Compliance with ethical standards
Conflict of interest
The authors certify that there is no conflict of interest regarding this manuscript.
Research involving human participants and/or animals
This article does not contain any studies with human participants or animals performed by any of the authors.
For this type of study, formal consent is not required.
- 1.Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66(2):115–32.Google Scholar
- 2.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.Google Scholar
- 3.Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7–30.Google Scholar
- 4.D’Alterio C, Nasti G, Polimeno M, Ottaiano A, Conson M, Circelli L, et al. CXCR4-CXCL12-CXCR7, TLR2-TLR4, and PD-1/PD-L1 in colorectal cancer liver metastases from neoadjuvant-treated patients. Oncoimmunology. 2016;5(12):10.Google Scholar
- 5.Yothers G, O’Connell MJ, Allegra CJ, Kuebler JP, Colangelo LH, Petrelli NJ, et al. Oxaliplatin as adjuvant therapy for colon cancer: updated results of NSABP C-07 trial, including survival and subset analyses. J Clin Oncol. 2011;29(28):3768–74.Google Scholar
- 6.Tournigand C, Andre T, Bonnetain F, Chibaudel B, Lledo G, Hickish T, et al. Adjuvant therapy with fluorouracil and oxaliplatin in stage II and elderly patients (between ages 70 and 75 years) with colon cancer: subgroup analyses of the Multicenter International Study of Oxaliplatin, Fluorouracil, and Leucovorin in the Adjuvant Treatment of Colon Cancer trial. J Clin Oncol. 2012;30(27):3353–60.Google Scholar
- 7.Tural D, Selcukbiricik F, Yildiz O, Elcin O, Erdamar S, Guney S, et al. Preoperative versus postoperative chemoradiotherapy in stage T3, N0 rectal cancer. Int J Clin Oncol. 2014;19(5):889–96.Google Scholar
- 8.Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–64.Google Scholar
- 9.Zou W, Wolchok JD, Chen L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers, and combinations. Sci Transl Med. 2016;8(328):328rv4.Google Scholar
- 10.Qorraj M, Bruns H, Bottcher M, Weigand L, Saul D, Mackensen A, et al. The PD-1/PD-L1 axis contributes to immune metabolic dysfunctions of monocytes in chronic lymphocytic leukemia. Leukemia. 2017;31(2):470–8.Google Scholar
- 11.Perez-Gracia JL, Labiano S, Rodriguez-Ruiz ME, Sanmamed MF, Melero I. Orchestrating immune check-point blockade for cancer immunotherapy in combinations. Curr Opin Immunol. 2014;27(1):89–97.Google Scholar
- 12.Cantoni C, Huergo-Zapico L, Parodi M, Pedrazzi M, Mingari MC, Moretta A, et al. NK cells, Tumor cell transition, and tumor progression in solid malignancies: new hints for NK-based immunotherapy? J Immunol Res. 2016;2016:4684268.Google Scholar
- 13.Page DB, Postow MA, Callahan MK, Allison JP, Wolchok JD. Immune modulation in cancer with antibodies. Annu Rev Med. 2014;65:185–92.Google Scholar
- 14.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.Google Scholar
- 15.Cierna Z, Mego M, Miskovska V, Machalekova K, Chovanec M, Svetlovska D, 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.Google Scholar
- 16.Meng XJ, Huang ZQ, Teng FF, Xing LG, Yu JM. Predictive biomarkers in PD-1/PD-L1 checkpoint blockade immunotherapy. Cancer Treat Rev. 2015;41(10):868–76.Google Scholar
- 17.Zheng P, Zhou Z. Human Cancer Immunotherapy with PD-1/PD-L1 Blockade. Biomark Cancer. 2015;7(Suppl 2):15–8.Google Scholar
- 18.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. J Clin Epidemiol. 2009;62(10):e1–34.Google Scholar
- 19.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.Google Scholar
- 20.Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Statistics Med. 1998;17(24):2815–34.Google Scholar
- 21.DerSimonian R, Laird N. Meta-analysis in clinical trials revisited. Contemp Clin Trials. 2015;45(Pt A):139–45.Google Scholar
- 22.Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50(4):1088–101.Google Scholar
- 23.Stuck AE, Rubenstein LZ, Wieland D. Bias in meta-analysis detected by a simple, graphical test. Asymmetry detected in funnel plot was probably due to true heterogeneity. BMJ (Clinical Res Ed). 1998;316(7129):469;author reply 470–71.Google Scholar
- 24.Zhu M, Sun J, Wang H, Mao Y, Wu YY, Zhang XG. Expressions of co inhibitory molecules B7 H1 and B7 H4 in colorectal carcinoma and their clinical significances. Chinese J Cancer Biother. 2011;18(5):528–32.Google Scholar
- 25.Droeser RA, Hirt C, Viehl CT, Frey DM, Nebiker C, Huber X, et al. Clinical impact of programmed cell death ligand 1 expression in colorectal cancer. Eur J cancer (Oxford, England: 1990). 2013;49(9):2233–42.Google Scholar
- 26.Shi S-J, Wang L-J, Wang G-D, Guo Z-Y, Wei M, Meng Y-L, et al. B7–H1 expression is associated with poor prognosis in colorectal carcinoma and regulates the proliferation and invasion of HCT116 colorectal cancer cells. Plos One. 2013;8(10):e76012.Google Scholar
- 27.Song M, Chen D, Lu B, Wang C, Zhang J, Huang L, et al. PTEN loss increases PD-L1 protein expression and affects the correlation between PD-L1 expression and clinical parameters in colorectal cancer. PLoS One. 2013;8(6):e65821.Google Scholar
- 28.Liang M, Li J, Wang D, Li S, Sun Y, Sun T, et al. T-cell infiltration and expressions of T lymphocyte co-inhibitory B7-H1 and B7-H4 molecules among colorectal cancer patients in northeast China’s Heilongjiang province. Tumor Biol. 2014;35(1):55–60.Google Scholar
- 29.Li XF, Liu XF, Yang YY, Liu AY, Zhang MY, Bai XF, et al. Correlation study of Bcl-2, B7-H1, EGFR, VEGF and colorectal cancer. Am J Cancer Res. 2015;5(7):2277–84.Google Scholar
- 30.Zhu H, Qin H, Huang Z, Li S, Zhu X, He J, et al. Clinical significance of programmed death ligand-1 (PD-L1) in colorectal serrated adenocarcinoma. Int J Clin Exp Pathol. 2015;8(8):9351–9.Google Scholar
- 31.Kim JH, Park HE, Cho NY, Lee HS, Kang GH. Characterisation of PD-L1-positive subsets of microsatellite-unstable colorectal cancers. Br J Cancer. 2016;115(4):490–6.Google Scholar
- 32.Koganemaru S, Inoshita N, Miura Y, Fukui Y, Ozaki Y, Tomizawa K, et al. Prognostic value of programmed death-ligand 1 (PD-L1) expression in patients with stage III colorectal cancer. J Clin Oncol. 2016;34.Google Scholar
- 33.Lee LH, Cavalcanti MS, Sega NH, Hechtman JF, Weiser MR, Smith JJ, et al. Patterns and prognostic relevance of PD-1 and PD-L1 expression in colorectal carcinoma. Mod Pathol. 2016;29(11):1433–42.Google Scholar
- 34.Li Y, Liang L, Dai W, Cai G, Xu Y, Li X, et al. Prognostic impact of programed cell death-1 (PD-1) and PD-ligand 1 (PD-L1) expression in cancer cells and tumor infiltrating lymphocytes in colorectal cancer. Mol Cancer. 2016;15(1):55.Google Scholar
- 35.Wang L, Ren F, Wang Q, Baldridge LA, Monn MF, Fisher KW, et al. Significance of programmed death ligand 1 (PD-L1) immunohistochemical expression in colorectal cancer. Mol Diagnosis Ther. 2016;20(2):175–81.Google Scholar
- 36.Lee KS, Kwak Y, Ahn S, Shin E, Oh HK, Kim DW, et al. Prognostic implication of CD274 (PD-L1) protein expression in tumor-infiltrating immune cells for microsatellite unstable and stable colorectal cancer. Cancer Immunol Immunother. 2017;66(7):927–39.Google Scholar
- 37.Korehisa S, Oki E, Iimori M, Nakaji Y, Shimokawa M, Saeki H, et al. Clinical significance of programmed cell death-ligand 1 expression and the immune microenvironment at the invasive front of colorectal cancers with high microsatellite instability. Int J Cancer. 2018;142(4):822–32.Google Scholar
- 38.Lee SJ, Jun SY, Lee IH, Kang BW, Park SY, Kim HJ, et al. CD274, LAG3, and IDO1 expressions in tumor-infiltrating immune cells as prognostic biomarker for patients with MSI-high colon cancer. J Cancer Res Clin Oncol. 2018;144(6):1005–14.Google Scholar
- 39.Masugi Y, Nishihara R, Yang J, Mima K, Da Silva A, Shi Y, et al. Tumour CD274 (PD-L1) expression and T cells in colorectal cancer. Gut. 2017;66(8):1463–73.Google Scholar
- 40.Bae SU, Jeong WK, Baek SK, Kim NK, Hwang I. Prognostic impact of programmed cell death ligand 1 expression on long-term oncologic outcomes in colorectal cancer. Oncol Lett. 2018;16(4):5214–22.Google Scholar
- 41.Berntsson J, Eberhard J, Nodin B, Leandersson K, Larsson AH, Jirström K. Expression of programmed cell death protein 1 (PD-1) and its ligand PD-L1 in colorectal cancer: relationship with sidedness and prognosis. OncoImmunology. 2018;7(8):e1465165.Google Scholar
- 42.Enkhbat T, Nishi M, Takasu C, Yoshikawa K, Jun H, Tokunaga T, et al. Programmed cell death ligand 1 expression is an independent prognostic factor in colorectal cancer. Anticancer Res. 2018;38(6):3367–73.Google Scholar
- 43.Duval S, Tweedie R. Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics. 2000;56(2):455–63.Google Scholar
- 44.Ioannidis JP, Trikalinos TA. The appropriateness of asymmetry tests for publication bias in meta-analyses: a large survey. CMAJ. 2007;176(8):1091–6.Google Scholar
- 45.Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480(7378):480–9.Google Scholar
- 46.Abdel-Rahman O. PD-L1 expression and outcome of advanced melanoma patients treated with anti-PD-1/PD-L1 agents: a meta-analysis. Immunotherapy. 2016;8(9):1081–9.Google Scholar
- 47.Zhou C, Tang J, Sun H, Zheng X, Li Z, Sun T, et al. PD-L1 expression as poor prognostic factor in patients with non-squamous non-small cell lung cancer. Oncotarget. 2017;8(35):58457–68.Google Scholar
- 48.Huang Y, Zhang SD, McCrudden C, Chan KW, Lin Y, Kwok HF. The prognostic significance of PD-L1 in bladder cancer. Oncol Rep. 2015;33(6):3075–84.Google Scholar
- 49.Xu F, Feng G, Zhao H, Liu F, Xu L, Wang Q, et al. Clinicopathologic significance and prognostic value of b7 homolog 1 in gastric cancer: a systematic review and meta-analysis. Medicine. 2015;94(43):e1911.Google Scholar
- 50.Huang B, Chen L, Bao C, Sun C, Li J, Wang L, et al. The expression status and prognostic significance of programmed cell death 1 ligand 1 in gastrointestinal tract cancer: a systematic review and meta-analysis. Onco Targets Ther. 2015;8:2617–25.Google Scholar
- 51.Dai C, Wang M, Lu J, Dai Z, Lin S, Yang P, et al. Prognostic and predictive values of PD-L1 expression in patients with digestive system cancer: a meta-analysis. Onco Targets Ther. 2017;10:3625–34.Google Scholar