PD-L1表达与食管癌患者临床特征及预后关系的Meta分析
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摘要
目的应用Meta分析方法探讨程序性死亡受体配体1(PDCD1LG1,PD-L1)在食管癌中的表达及其临床意义。方法指定文献纳入和排除标准,设计检索策略,通过PubMed、EMBASE、Medline和Cochrane临床对照试验中心注册数据库(CENTRAL)检索关于PD-L1表达与食管癌患者临床特征和总生存情况关系的随机对照研究、病例对照研究和队列研究,筛选文献,提取数据,纳入研究的方法学质量采用纽卡斯尔-渥太华量表(NOS)进行评价。结果共纳入12项研究(包括2122例食管癌患者),汇总分析结果显示,PD-L1表达与食管癌患者的不良预后可能有关(P﹤0.01),死亡风险增加45%。对11项研究(包括2021例食管鳞状细胞癌患者)进行亚组分析,结果显示,PD-L1表达与食管鳞状细胞癌患者的不良预后可能有关(P﹤0.01),死亡风险增加39%。远处转移、晚期(Ⅳ期)与食管癌患者食管癌组织中PD-L1的表达均有关(P﹤0.05),与食管癌位置为中上段可能有关(P=0.05),但与患者的性别、分化程度、浸润深度和淋巴结转移情况均无关(P﹥0.05)。结论 PD-L1可能是食管癌患者预后的重要预测指标,且有助于临床医师更好地筛查程序性死亡因子通路阻滞剂的潜在受益人群。
Objective The expression of programmed cell death 1 ligand 1(PD-L1) in esophageal cancer(EC) and its clinical significance were investigated by Meta-analysis. Method By setting up inclusion and exclusion criteria,search strategies were established for the PubMed, EMBASE, Medline and the ochrane central register of controlled trials(CENTRAL) to retrieve randomized controlled trials, case-control study, and cohort studies that investigated the relationship between pathological features and overall survival(OS) in PD-L1 positive and PD-L1 negative patients with EC.Methodological quality was assessed with the Newcastle-Ottawa scale(NOS). Result A total of 2122 patients in 12 studies were included in this Meta-analysis. Summary analysis results indicated that PD-L1 expression was possibly associated with a shorter OS(P<0.01), increased risk of death by 45%. In subgroup analysis, 11 studies consisting of 2021 esophageal squamous cell carcinoma patients were included in the Meta-analysis, and the results showed that the expression of PD-L1 was likely associated with poor OS in esophageal squamous cell carcinoma patients(P<0.01), increased risk of death by 39%. Distal metastasis and advanced stage(stage IV) were associated with the expression of PD-L1(P<0.05),and upper and middle esophageal cancer was probably associated with the expression of PD-L1(P=0.05). However, the expression of PD-L1 was independent of gender, degree of differentiation, depth of invasion, and lymph node metastasis(P>0.05). Conclusion This Meta-analysis indicates that the expression of PD-L1 is a valuable predictor for the prognosis of esophageal cancer patients, and it may be helpful for clinicians to better screen candidates who might benefit from PD pathway blockade.
Objective The expression of programmed cell death 1 ligand 1(PD-L1) in esophageal cancer(EC) and its clinical significance were investigated by Meta-analysis. Method By setting up inclusion and exclusion criteria,search strategies were established for the PubMed, EMBASE, Medline and the ochrane central register of controlled trials(CENTRAL) to retrieve randomized controlled trials, case-control study, and cohort studies that investigated the relationship between pathological features and overall survival(OS) in PD-L1 positive and PD-L1 negative patients with EC.Methodological quality was assessed with the Newcastle-Ottawa scale(NOS). Result A total of 2122 patients in 12 studies were included in this Meta-analysis. Summary analysis results indicated that PD-L1 expression was possibly associated with a shorter OS(P<0.01), increased risk of death by 45%. In subgroup analysis, 11 studies consisting of 2021 esophageal squamous cell carcinoma patients were included in the Meta-analysis, and the results showed that the expression of PD-L1 was likely associated with poor OS in esophageal squamous cell carcinoma patients(P<0.01), increased risk of death by 39%. Distal metastasis and advanced stage(stage IV) were associated with the expression of PD-L1(P<0.05),and upper and middle esophageal cancer was probably associated with the expression of PD-L1(P=0.05). However, the expression of PD-L1 was independent of gender, degree of differentiation, depth of invasion, and lymph node metastasis(P>0.05). Conclusion This Meta-analysis indicates that the expression of PD-L1 is a valuable predictor for the prognosis of esophageal cancer patients, and it may be helpful for clinicians to better screen candidates who might benefit from PD pathway blockade.
引文
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[9] Xia H, Shen J, Hu F, et al. PD-L1 over-expression is associated with a poor prognosis in Asian non-small cell lung cancer patients[J]. Clin Chim Acta, 2017, 469:191-194.
[10] Xu F, Xu L, Wang Q, et al. Clinicopathological and prognostic value of programmed death ligand-1(PD-L1)in renal cell carcinoma:a meta-analysis[J]. Int J Clin Exp Med, 2015, 8(9):14595-14603.
[11] Zhang M, Dong Y, Liu H, et al. The clinicopathological and prognostic significance of PD-L1 expression in gastric cancer:a meta-analysis of 10 studies with 1,901 patients[J]. Sci Rep, 2016, 6:37933.
[12] Zhang M, Sun H, Zhao S, et al. Expression of PD-L1 and prognosis in breast cancer:a meta-analysis[J]. Oncotarget,2017, 8(19):31347-31354.
[13] Parmar MK, TorriV, Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints[J]. Stat Med, 1998, 17(24):2815-2834.
[14] Loos M, Langer R, Schuster T, et al. Clinical significance of the costimulatory molecule B7-H1 in Barrett carcinoma[J]. Ann Thorac Surg, 2011, 91(4):1025-1031.
[15] Ohigashi Y, Sho M, Yamada Y, et al. Clinical significance of programmed death-1 ligand-1 and programmed death-1ligand-2 expression in human esophageal cancer[J]. Clin Cancer Res, 2005, 11(8):2947-2953.
[16] Chen K, Cheng G, Zhang F, et al. Prognostic significance of programmed death-1 and programmed death-ligand 1expression in patients with esophageal squamous cell carcinoma[J]. Oncotarget, 2016, 7(21):30772-30780.
[17] Chen L, Deng H, Lu M, et al. B7-H1 expression associates with tumor invasion and predicts patient’s survival in human esophageal cancer[J]. Int J Clin Exp Pathol, 2014, 7(9):6015-6023.
[18] Chen MF, Chen PT, Chen WC, et al. The role of PD-L1 in the radiation response and prognosis for esophageal squamous cell carcinoma related to IL-6 and T-cell immunosuppression[J]. Oncotarget, 2016, 7(7):7913-7924.
[19] Hatogai K, Kitano S, Fujii S, et al. Comprehensive immunohistochemical analysis of tumor microenvironment immune status in esophageal squamous cell carcinoma[J].Oncotarget, 2016, 7(30):47252-47264.
[20] Ito S, Okano S, Morita M, et al. Expression of PD-L1 and HLA class I in esophageal squamous cell carcinoma:prognostic factors for patient outcome[J]. Ann Surg Oncol,2016, 23(Suppl 4):508-515.
[21] Kim R, Keam B, Kwon D, et al. Programmed death ligand-1 expression and its prognostic role in esophageal squamous cell carcinoma[J]. World J Gastroenterol, 2016, 22(37):8389-8397.
[22] Leng C, Li Y, Qin J, et al. Relationship between expression of PD-L1 and PD-L2 on esophageal squamous cell carcinoma and the antitumor effects of CD8+T cells[J].Oncol Rep, 2016, 35(2):699-708.
[23] Tanaka K, Miyata H, Sugimura K, et al. Negative influence of programmed death-1-ligands on the survival of esophageal cancer patients treated with chemotherapy[J].Cancer Sci, 2016, 107(6):726-733.
[24] Zhu Y, Li M, Mu D, et al. CD8+/FOXP3+ratio and PD-L1expression associated with survival in pT3N0M0 stage esophageal squamous cell cancer[J]. Oncotarget, 2016, 7(44):71455-71465.
[25] Jiang D, Song Q, Wang H, et al. Independent prognostic role of PD-L1 expression in patients with esophageal squamous cell carcinoma[J]. Oncotarget, 2017, 8(5):8315-8329.
[26] Jin Y, Zhao J, Shi X, et al. Prognostic value of programed death ligand 1 in patients with solid tumors:a meta-analysis[J]. J Cancer Res Ther, 2015, 11 Suppl 1:C38-C43.
[27] Qu HX, Zhao LP, Zhan SH, et al. Clinicopathological and prognostic significance of programmed cell death ligand 1(PD-L1)expression in patients with esophageal squamous cell carcinoma:a meta-analysis[J]. J Thorac Dis, 2016, 8(11):3197-3204.
[28]马丽莉,李水仙,毕志彬. PD-L1和PD-L2在食管鳞状细胞癌表达增强并与浸润和转移有关[J].细胞与分子免疫学杂志, 2015, 31(8):1112-1114.
[29] Jiang YB, Anthony W.I. Lo, Wong A, et al. Prognostic significance of tumor-infiltrating immune cells and PD-L1expression in oesphageal squamous cell carcinoma[J]. Oncotarget, 2017, 8(18):30175-30189.
[30] Zou W, Chen L. Inhibitory B7-family molecules in the tumourmicroenvironment[J]. Nat Rev Immunol, 2008, 8(6):467-477.
[31] Zou W, Wolchok JD, Chen L. PD-L1(B7-H1)and PD-1pathway blockade for cancer therapy:Mechanisms, response biomarkers, and combinations[J]. Sci Transl Med,2016, 8(328):328rv4.
[32] Gandini S, Massi D, MandalàM. PD-L1 expression in cancer patients receiving anti PD-1/PD-L1 antibodies:a systematic review and meta-analysis[J]. Crit Rev Oncol Hematol, 2016, 100:88-98.
[33] Ott PA, Bang YJ, Berton-Rigaud D, et al. Safety and antitumor activity of pembrolizumab in advanced programmed death ligand 1-positive endometrial cancer:results from the KEYNOTE-028 study[J]. J Clin Oncol,2017, 35(22):2535-2541.
[34] Doi T, Piha-Paul SA, Jalal SI, et al. Updated results for the advanced esophageal carcinoma cohort of the phase Ib KEYNOTE-028 study of pembrolizumab(MK-3475)[J]. J Clin Oncol, 34(4_suppl):7.
[35] Le DT, Bendell JC, Calvo E. Safety and activity of nivolumabmonotherapy in advanced and metastatic(A/M)gastric or gastroesophageal junction cancer(GC/GEC):results from the CheckMate-032 study[J]. J Clin Oncol, 34(4_suppl):8.
[2] Jemal A, Bray F, Center MM, et al. Global cancer statistics[J]. CA Cancer J Clin, 2011, 61(2):69-90.
[3] Medical Research Council Oesophageal Cancer Working Group. Surgical resection with or without preoperative chemotherapy in oesophageal cancer:a randomised controlled trial[J]. Lancet, 2002, 359(9319):1727-1733.
[4] Hansen JD, Du Pasquier L, Lefranc MP, et al. The B7 family of immunoregulatory receptors:a comparative and evolutionary perspective[J]. MolImmunol, 2009, 46(3):457-472.
[5] Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy[J]. Nat Rev Cancer, 2012, 12(4):252-264.
[6] Sanmamed MF, Chen L. Inducible expression of B7-H1(PD-L1)and its selective role in tumor site immune modulation[J]. Cancer J, 2014, 20(4):256-261.
[7] Francisco LM, Salinas VH, Brown KE, et al. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells[J]. J Exp Med, 2009, 206(13):3015-3029.
[8] Huang B, Chen L, Bao C, et al. The expression status and prognostic significance of programmed cell death 1 ligand1 in gastrointestinal tract cancer:a systematic review and meta-analysis[J]. Onco Targets Ther, 2015, 8:2617-2625.
[9] Xia H, Shen J, Hu F, et al. PD-L1 over-expression is associated with a poor prognosis in Asian non-small cell lung cancer patients[J]. Clin Chim Acta, 2017, 469:191-194.
[10] Xu F, Xu L, Wang Q, et al. Clinicopathological and prognostic value of programmed death ligand-1(PD-L1)in renal cell carcinoma:a meta-analysis[J]. Int J Clin Exp Med, 2015, 8(9):14595-14603.
[11] Zhang M, Dong Y, Liu H, et al. The clinicopathological and prognostic significance of PD-L1 expression in gastric cancer:a meta-analysis of 10 studies with 1,901 patients[J]. Sci Rep, 2016, 6:37933.
[12] Zhang M, Sun H, Zhao S, et al. Expression of PD-L1 and prognosis in breast cancer:a meta-analysis[J]. Oncotarget,2017, 8(19):31347-31354.
[13] Parmar MK, TorriV, Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints[J]. Stat Med, 1998, 17(24):2815-2834.
[14] Loos M, Langer R, Schuster T, et al. Clinical significance of the costimulatory molecule B7-H1 in Barrett carcinoma[J]. Ann Thorac Surg, 2011, 91(4):1025-1031.
[15] Ohigashi Y, Sho M, Yamada Y, et al. Clinical significance of programmed death-1 ligand-1 and programmed death-1ligand-2 expression in human esophageal cancer[J]. Clin Cancer Res, 2005, 11(8):2947-2953.
[16] Chen K, Cheng G, Zhang F, et al. Prognostic significance of programmed death-1 and programmed death-ligand 1expression in patients with esophageal squamous cell carcinoma[J]. Oncotarget, 2016, 7(21):30772-30780.
[17] Chen L, Deng H, Lu M, et al. B7-H1 expression associates with tumor invasion and predicts patient’s survival in human esophageal cancer[J]. Int J Clin Exp Pathol, 2014, 7(9):6015-6023.
[18] Chen MF, Chen PT, Chen WC, et al. The role of PD-L1 in the radiation response and prognosis for esophageal squamous cell carcinoma related to IL-6 and T-cell immunosuppression[J]. Oncotarget, 2016, 7(7):7913-7924.
[19] Hatogai K, Kitano S, Fujii S, et al. Comprehensive immunohistochemical analysis of tumor microenvironment immune status in esophageal squamous cell carcinoma[J].Oncotarget, 2016, 7(30):47252-47264.
[20] Ito S, Okano S, Morita M, et al. Expression of PD-L1 and HLA class I in esophageal squamous cell carcinoma:prognostic factors for patient outcome[J]. Ann Surg Oncol,2016, 23(Suppl 4):508-515.
[21] Kim R, Keam B, Kwon D, et al. Programmed death ligand-1 expression and its prognostic role in esophageal squamous cell carcinoma[J]. World J Gastroenterol, 2016, 22(37):8389-8397.
[22] Leng C, Li Y, Qin J, et al. Relationship between expression of PD-L1 and PD-L2 on esophageal squamous cell carcinoma and the antitumor effects of CD8+T cells[J].Oncol Rep, 2016, 35(2):699-708.
[23] Tanaka K, Miyata H, Sugimura K, et al. Negative influence of programmed death-1-ligands on the survival of esophageal cancer patients treated with chemotherapy[J].Cancer Sci, 2016, 107(6):726-733.
[24] Zhu Y, Li M, Mu D, et al. CD8+/FOXP3+ratio and PD-L1expression associated with survival in pT3N0M0 stage esophageal squamous cell cancer[J]. Oncotarget, 2016, 7(44):71455-71465.
[25] Jiang D, Song Q, Wang H, et al. Independent prognostic role of PD-L1 expression in patients with esophageal squamous cell carcinoma[J]. Oncotarget, 2017, 8(5):8315-8329.
[26] Jin Y, Zhao J, Shi X, et al. Prognostic value of programed death ligand 1 in patients with solid tumors:a meta-analysis[J]. J Cancer Res Ther, 2015, 11 Suppl 1:C38-C43.
[27] Qu HX, Zhao LP, Zhan SH, et al. Clinicopathological and prognostic significance of programmed cell death ligand 1(PD-L1)expression in patients with esophageal squamous cell carcinoma:a meta-analysis[J]. J Thorac Dis, 2016, 8(11):3197-3204.
[28]马丽莉,李水仙,毕志彬. PD-L1和PD-L2在食管鳞状细胞癌表达增强并与浸润和转移有关[J].细胞与分子免疫学杂志, 2015, 31(8):1112-1114.
[29] Jiang YB, Anthony W.I. Lo, Wong A, et al. Prognostic significance of tumor-infiltrating immune cells and PD-L1expression in oesphageal squamous cell carcinoma[J]. Oncotarget, 2017, 8(18):30175-30189.
[30] Zou W, Chen L. Inhibitory B7-family molecules in the tumourmicroenvironment[J]. Nat Rev Immunol, 2008, 8(6):467-477.
[31] Zou W, Wolchok JD, Chen L. PD-L1(B7-H1)and PD-1pathway blockade for cancer therapy:Mechanisms, response biomarkers, and combinations[J]. Sci Transl Med,2016, 8(328):328rv4.
[32] Gandini S, Massi D, MandalàM. PD-L1 expression in cancer patients receiving anti PD-1/PD-L1 antibodies:a systematic review and meta-analysis[J]. Crit Rev Oncol Hematol, 2016, 100:88-98.
[33] Ott PA, Bang YJ, Berton-Rigaud D, et al. Safety and antitumor activity of pembrolizumab in advanced programmed death ligand 1-positive endometrial cancer:results from the KEYNOTE-028 study[J]. J Clin Oncol,2017, 35(22):2535-2541.
[34] Doi T, Piha-Paul SA, Jalal SI, et al. Updated results for the advanced esophageal carcinoma cohort of the phase Ib KEYNOTE-028 study of pembrolizumab(MK-3475)[J]. J Clin Oncol, 34(4_suppl):7.
[35] Le DT, Bendell JC, Calvo E. Safety and activity of nivolumabmonotherapy in advanced and metastatic(A/M)gastric or gastroesophageal junction cancer(GC/GEC):results from the CheckMate-032 study[J]. J Clin Oncol, 34(4_suppl):8.