胃癌组织中驻留CD8~+T细胞的浸润程度及其意义
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摘要
目的研究组织驻留CD8~+T细胞(CD103~+CD8~+T细胞)在胃癌组织中的浸润程度及分布特征,并分析其浸润程度与患者临床病理特征及预后的关系。方法采用组织芯片技术和免疫荧光染色法分别检测90例胃癌及相应癌旁正常组织中CD8~+T细胞及CD103~+CD8~+T细胞的浸润分布特征及程度,采用Wilcoxon秩和检验比较胃癌及癌旁正常组织中CD8~+T细胞、CD103~+CD8~+T细胞浸润程度及CD103~+CD8~+T细胞占CD8~+T细胞比率的差异,χ~2检验分析胃癌组织中CD8~+T细胞、CD103~+CD8~+T细胞浸润程度及CD103~+CD8~+T细胞占CD8~+T细胞比率与患者临床病理特征的关系,采用Kaplan-Meier生存分析法分析CD8~+T细胞、CD103~+CD8~+T细胞浸润程度及CD103~+CD8~+T细胞占CD8~+T细胞比率与患者预后的关系,拟合Cox模型评价不同指标与患者预后的关系。结果胃癌组织CD103~+CD8~+T细胞浸润程度与癌旁正常组织比较,差异无统计学意义(P>0.05)。Ⅲ～Ⅳ期胃癌患者中CD103~+CD8~+T细胞高度浸润的比率(69.09%,38/55)显著低于Ⅰ～Ⅱ期胃癌患者(91.43%,32/35),差异有统计学意义(χ~2=6.175,P=0.013)。CD103~+CD8~+T细胞浸润程度与患者其他临床病理特征相关性无统计学意义(P>0.05)。Kaplan-Merier生存分析显示,CD103~+CD8~+T细胞高度浸润的患者总生存期较CD103~+CD8~+T细胞低度浸润的患者显著延长(HR=2.187,95%CI:1.062～4.500,P=0.033 6);多因素Cox比例风险模型显示,肿瘤直径(HR=2.031,95%CI:1.163～3.546,P=0.013)和CD103~+CD8~+T细胞浸润程度(HR=0.516,95%CI:0.285～0.934,P=0.029)均可作为胃癌患者的独立预后因素。结论 CD103~+CD8~+T细胞在胃癌组织中与良好预后有关,提示其在抑制胃癌发生发展过程中发挥重要作用,可作为胃癌患者预后评估的指标。
Objective To investigate the degree of infiltration and distribution of tissue-resident CD8~+T cells(CD103~+CD8~+ T cells) in gastric cancer tissues, and analyze the relationship between the degree of infiltration and clinicopathological features and prognosis. Methods Tissue microarray and immunofluorescence staining were used to examine the CD8~+ T cells and CD103~+CD8~+ T cells infiltration in 90 cases of gastric cancer and their adjacent normal tissues. Wilcoxon rank test was used to compare the CD8~+ T cells, CD103~+CD8~+ T cells infiltration and CD103~+CD8~+ T cells/CD8~+ T cells ratio in gastric cancer and corresponding normal tissues. The chi-square test was used to analyze the relationship between CD8~+ T cells, CD103~+CD8~+ T cells infiltration and CD103~+CD8~+ T cells/CD8~+ T cells ratio in gastric cancer tissues and clinicopathological features of the patients. Kaplan-Meier survival analysis was performed to explore the correlation between CD8~+ T cells, CD103~+CD8~+ T cells infiltration and CD103~+CD8~+ T cells/CD8~+ T cells ratio and overall survival. Cox model was used to analyze the correlation between different clinical parameters and prognosis of the patients. Results There was no significant difference for the infiltration of CD103~+CD8~+ T cells between the gastric cancer tissues and adjacent normal tissues(P>0.05). The infiltration rate of CD103~+CD8~+ T cells in the cases in stage Ⅲ to Ⅳ(69.09%, 38/55) was significantly lower than that in the stage Ⅰ to Ⅱ cases(91.43%, 32/35),(χ~2=6.175, P=0.013). There was no significant correlation between CD103~+CD8~+ T cells infiltration and other clinicopathological features(P>0.05). Kaplan-Meier survival analysis showed that the patients with high CD103~+CD8~+ T cells infiltration showed significantly longer overall survival than the patients with low CD103~+CD8~+ T cells infiltration(HR=2.187, 95%CI: 1.062-4.500, P=0.033 6). Multivariate Cox model analysis indicated that tumor diameter(HR=2.031, 95%CI: 1.163-3.546, P=0.013) and CD103~+CD8~+ T cells infiltration(HR=0.516, 95%CI: 0.285-0.934, P=0.029) were independent prognostic factors for gastric cancer. Conclusion CD103~+CD8~+ T cells in gastric cancer tissues should be associated with good prognosis, suggesting that they play an important role in the inhibition of gastric carcinogenesis and development, and can be used as an important factor for the prognosis evaluation of the patients with gastric cancer.
Objective To investigate the degree of infiltration and distribution of tissue-resident CD8~+T cells(CD103~+CD8~+ T cells) in gastric cancer tissues, and analyze the relationship between the degree of infiltration and clinicopathological features and prognosis. Methods Tissue microarray and immunofluorescence staining were used to examine the CD8~+ T cells and CD103~+CD8~+ T cells infiltration in 90 cases of gastric cancer and their adjacent normal tissues. Wilcoxon rank test was used to compare the CD8~+ T cells, CD103~+CD8~+ T cells infiltration and CD103~+CD8~+ T cells/CD8~+ T cells ratio in gastric cancer and corresponding normal tissues. The chi-square test was used to analyze the relationship between CD8~+ T cells, CD103~+CD8~+ T cells infiltration and CD103~+CD8~+ T cells/CD8~+ T cells ratio in gastric cancer tissues and clinicopathological features of the patients. Kaplan-Meier survival analysis was performed to explore the correlation between CD8~+ T cells, CD103~+CD8~+ T cells infiltration and CD103~+CD8~+ T cells/CD8~+ T cells ratio and overall survival. Cox model was used to analyze the correlation between different clinical parameters and prognosis of the patients. Results There was no significant difference for the infiltration of CD103~+CD8~+ T cells between the gastric cancer tissues and adjacent normal tissues(P>0.05). The infiltration rate of CD103~+CD8~+ T cells in the cases in stage Ⅲ to Ⅳ(69.09%, 38/55) was significantly lower than that in the stage Ⅰ to Ⅱ cases(91.43%, 32/35),(χ~2=6.175, P=0.013). There was no significant correlation between CD103~+CD8~+ T cells infiltration and other clinicopathological features(P>0.05). Kaplan-Meier survival analysis showed that the patients with high CD103~+CD8~+ T cells infiltration showed significantly longer overall survival than the patients with low CD103~+CD8~+ T cells infiltration(HR=2.187, 95%CI: 1.062-4.500, P=0.033 6). Multivariate Cox model analysis indicated that tumor diameter(HR=2.031, 95%CI: 1.163-3.546, P=0.013) and CD103~+CD8~+ T cells infiltration(HR=0.516, 95%CI: 0.285-0.934, P=0.029) were independent prognostic factors for gastric cancer. Conclusion CD103~+CD8~+ T cells in gastric cancer tissues should be associated with good prognosis, suggesting that they play an important role in the inhibition of gastric carcinogenesis and development, and can be used as an important factor for the prognosis evaluation of the patients with gastric cancer.
引文
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[11]Komdeur FL,Wouters MC,Workel HH,et al.CD103+ intraepithelial T cells in high-grade serous ovarian cancer are phenotypically diverse TCRαβ+ CD8αβ+ T cells that can be targeted for cancer immunotherapy[J].Oncotarget,2016,7(46):75130-75144.
[12]Ganesan AP,Clarke J,Wood O,et al.Tissue-resident memory features are linked to the magnitude of cytotoxic T cell responses in human lung cancer[J].Nat Immunol,2017,18(8):940-950.
[2]Webb JR,Milne K,Nelson BH.Location,location,location:CD103 demarcates intraepithelial,prognostically favorable CD8+ tumor-infiltrating lymphocytes in ovarian cancer[J].Oncoimmunology,2014,3:e27668.
[3]Sarrabayrouse G,Corvaisier M,Ouisse LH,et al.Tumor-reactive CD4+ CD8αβ+CD103+ αβ T cells:a prevalent tumor-reactive T-cell subset in metastatic colorectal cancers[J].Int J Cancer,2011,128(12):2923-2932.
[4]Thom JT,Weber TC,Walton SM,et al.The salivary gland acts as a sink for tissue-resident memory CD8+ T cells,facilitating protection from local cytomegalovirus infection[J].Cell Rep,2015,13(6):1125-1136.
[5]Frost EL,Kersh AE,Evavold BD,et al.Cutting edge:resident memory CD8 T cells express high-affinity TCRs[J].J Immunol,2015,195(8):3520-3524.
[6]Iijima N,Iwasaki A.Tissue instruction for migration and retention of TRM cells[J].Trends Immunol,2015,36(9):556-564.
[7]Thom JT,Oxenius A.Tissue-resident memory T cells in cytomegalovirus infection[J].Curr Opin Virol,2016,16:63-69.
[8]Mackay LK,Wynne-Jones E,Freestone D,et al.T-box transcription factors combine with the cytokines TGF-β and IL-15 to control tissue-resident memory T cell fate[J].Immunity,2015,43(6):1101-1111.
[9]Le Floc′h A,Jalil A,Vergnon I,et al.αEβ7 integrin interaction with E-cadherin promotes antitumor CTL activity by triggering lytic granule polarization and exocytosis[J].J Exp Med,2007,204 (3):559-570.
[10]Franciszkiewicz K,Le Floc′h A,Jalil A,et al.Intratumoral induction of CD103 triggers tumor-specific CTL function and CCR5-dependent T-cell retention[J].Cancer Res,2009,69(15):6249-6255.
[11]Komdeur FL,Wouters MC,Workel HH,et al.CD103+ intraepithelial T cells in high-grade serous ovarian cancer are phenotypically diverse TCRαβ+ CD8αβ+ T cells that can be targeted for cancer immunotherapy[J].Oncotarget,2016,7(46):75130-75144.
[12]Ganesan AP,Clarke J,Wood O,et al.Tissue-resident memory features are linked to the magnitude of cytotoxic T cell responses in human lung cancer[J].Nat Immunol,2017,18(8):940-950.