摘要
目的 探讨CD8~+T细胞浸润及STAT1、pSTAT1、STAT3、pSTAT3蛋白表达与胃癌临床病理特征和预后的关系。方法 回顾性分析2008年7月至2011年12月行D_2根治性手术胃癌患者186例。采用免疫组化染色SP法对CD8~+T细胞浸润、STATs蛋白的表达,分析其表达与临床病理特征(性别、年龄、肿瘤部位、肿瘤分期、病理分级)的关系;Kaplan-miere法绘制生存曲线,Cox风险比例回归模型分析影响无病生存时间(DFS)和总生存时间(OS)的预后因素。结果 仅pSTAT3蛋白表达与胃癌病理分级有关(P=0.017)。186例胃癌患者中位DFS和OS分别为87.0个月(50.96～123.04个月)、91.0个月(68.31～113.69个月)。单因素分析显示:TNM分期、肿瘤部位、CD8~+T细胞浸润程度均与DFS和OS有关(P<0.05)。Cox风险比例回归模型分析显示:TNM分期、肿瘤部位、CD8~+T细胞浸润是DFS和OS的独立预后因素(P<0.05)。Spearman相关分析显示,CD8~+T细胞表达与pSTAT3、STAT3相关,相关系数分别为0.405、0.186(P<0.05)。结论 CD8~+T细胞浸润程度越高,患者预后越好。STATs(STAT1、pSTAT1、STAT3、pSTAT3)蛋白表达与胃癌临床病理特征、DFS和OS无关,pSTAT3、STAT3可能参与CD8~+T细胞抗肿瘤免疫环节。
Objective To detective expression of CD8~+T cell infiltration and expression of STAT1, pSTAT1, STAT3 and pSTAT3 proteins, and to investigate the relationship between protein expression and clinicopathological characteristics and prognosis of gastric cancer. Methods A retrospective analysis was made of 186 patients with gastric cancer who underwent radical D_2 surgery from July 2008 to December 2011. Immunohistochemical staining SP was used to detect the infiltration of CD8~+T cells and the expression of STATs protein. The relationship between its expression and clinicopathological features(sex, age, location, stage and pathological grade) was analyzed. Kaplan-miere method was used to draw survival curve. Cox proportional regression model was used to analyze the prognostic factors of disease-free survival(DFS) and overall survival time(OS).Results Only the expression of p-STAT3 protein was correlated with pathological grade(P=0.017). The median DFS and OS of 186 patients with gastric cancer were 87.0 months(50.96-123.04 months) and 91.0 months(68.31-113.69 months), respectively. Univariate analysis showed that TNM stage, tumor location and CD8~+T cell infiltration were related to DFS and OS(P<0.05). Cox proportional regression model showed that TNM stage, tumor location and CD8~+T cell infiltration were independent prognostic factors for DFS and OS(P<0.05). Spearman correlation analysis showed that the expression of CD8~+T cells was correlated with pSTAT3 and STAT3, with correlation coefficients of 0.405 and 0.186 respectively(P<0.05). Conclusion The higher the degree of CD8~+T cell infiltration, the better the prognosis of the patients with gastric cancer. The protein expression of STATs(STAT1, pSTAT1, STAT3, pSTAT3) is not related to clinicopathological factors, recurrence and prognosis of gastric cancer. pSTAT3 and STAT3 may participate in the anti-tumor immunity of CD8~+T cells.
引文
[1] Van Cutsem E,Sagaert X,Topal B,et al.Gastric cancer[J].Lancet,2016,388(10060):2654-2664.
[2] Shen L,Shan YS,Hu HM,et al.Management of gastric cancer in Asia:resource-stratified guidelines[J].Lancet oncol,2013,14(12):535-547.
[3] Muro K,Chung HC,Shankaran V,et al.Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012):a multicentre,open-label,phase 1b trial [J].Lancet Oncol,2016,17(6):717-726.
[4] Taube JM,Klein A,Brahmer JR,et al.Association of PD-1,PD-1 ligands,and other features of the tumor immune microenvironment with response to anti-PD-1 therapy[J].Clin Cancer Res,2014,20(19):5064-5074.
[5] Ihara S,Kida H,Arase H,et al.Inhibitory roles of signal transducer and activator of transcription 3 in antitumor immunity during carcinogen-induced lung tumorigenesis[J].Cancer Res,2012,72(12):2990-2999.
[6] Ock CY,Keam B,Kim S,et al.Pan-cancer immunogenomic perspective on the tumor microenvironment based on PD-L1 and CD8 T-cell infiltration[J].Clin Cancer Res,2016,22(9):2261-2270.
[7] Gibney GT,Weiner LM,Atkins MB.Predictive biomarkers for checkpoint inhibitor-based immunotherapy[J].Lancet Oncol,2016,17(12):542-551.
[8] Donnem T,Kilvaer TK,Andersen S,et al.Strategies for clinical implementation of TNM-Immunoscore in resected non-small cell lung cancer[J].Ann Oncol,2016,27(2):225-232.
[9] Salgado R,Denkert C,Demaria S,et al.The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer:recommendations by an International TILs Working Group 2014[J].Ann Oncol,2015,26(2):259-271.
[10] Xing X,Guo J,Wen X,et al.Analysis of PD1,PDL1,PDL2 expression and T cells infiltration in 1014 gastric cancer patients[J/OL].Oncoimmunology,2018[2019-01-22].https://www.ncbi.nlm.nih.gov/pubmed/29399387.
[11] Jiang YM,Zhang Q,Hu YE,et al.Immunoscore signature:A prognostic and predictive tool in gastric cancer[J].Ann Surg,2018,267(3):504-513.
[12] Kang YK,Boku N,Satoh T,et al.Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to,or intolerant of,at least two previous chemotherapy regimens (ONO-4538-12,ATTRACTION-2):a randomised,double-blind,placebo-controlled,phase 3 trial[J].Lancet,2017,390(10111):2461-2471.
[13] Fuchs CS,Doi T,Jang RW,et al.Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer:Phase 2 clinical KEYNOTE-059 trial[J/OL].Jama Oncol,2018 [2019-01-22].https://www.ncbi.nlm.nih.gov/pubmed/29543932.
[14] Shitara K,?zgüro?lu M,Bang YJ,et al.Pembrolizumab versus paclitaxel for previously treated,advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061):a randomised,open-label,controlled,phase 3 trial[J].Lancet,2018,392(10142):123-133.
[15] Tumeh PC,Harview CL,Yearly JH,et al.PD-1 blockade induces responses by inhibiting adaptive immune resistance[J].Nature,2014,515(7528):568-571.
[16] Gato-Caňas M,Zuazo M,Arasanz H,et al.PDL1 Signals through conserved sequence motifs to overcome interferon-mediated cytotoxicity[J].Cell Reports,2017,20(8):1818-1829.
[17] Karachaliou N,Gonzalez-Cao M,Crespo G,et al.Interferon gamma,an important marker of response to immune checkpoint blockade in non-small cell lung cancer and melanoma patients[J/OL].Ther Adv Med Oncol,2018[2019-01-22].http://europepmc.org/articles/PMC5784541/.
[18] Lee J,Kang WK,Park JO,et al.Expression of activated signal transducer and activator of transcription 3 predicts poor clinical outcome in gastric adenocarcinoma[J].APMIS,2009,117(8):598-606.
