FOXP3~+调节性T细胞在胃癌组织中的浸润及对胃癌根治术后患者生存的影响
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摘要
目的：研究肿瘤浸润淋巴细胞(Tumour-infiltrating lymphocytes, TILs)尤其是FOXP3+调节性T细胞(regulatory T cells, Tregs)在胃癌组织及淋巴结中的浸润情况,并探讨二者对胃癌患者根治术后生存的影响。
材料与方法：将135例于1999-2005期间在复旦大学附属中山医院行D2根治术胃癌患者的肿瘤组织和正常胃组织制成组织芯片,N1站淋巴结制成病理切片,利用免疫组化的方法,观察不同组织中CD4+、CD8+和FOXP3+ T细胞的浸润情况。利用中位值分组,应用多种统计学方法分析以上3种淋巴细胞与胃癌临床病理特点及患者D2根治术后生存之间的关系。
结果：胃癌肿瘤组织中FOXP3+ T细胞等3种TILs数目明显高于正常组织(配对差值非参检验,p值均小于0.01)；肿瘤内FOXP3+ T细胞浸润多的患者预后较差(Cox多因素生存分析HR=2.598,p=0.004),FOXP3+ T细胞浸润多的患者一年、两年、三年和四年生存率分别是82.6%、65.2%、60.4%和55.6%,而FOXP3+T细胞浸润少的患者一年、两年、三年和四年的生存率分别是83.3%、81.8%、77.3%和77.3%(Logrank检验p=0.009)；淋巴结内FOXP3+ T细胞的浸润数目与淋巴结转移负相关(卡方检验,p=0.043),但对预后无明显影响(Logrank检验p=0.257)。肿瘤内、肿瘤旁和淋巴结内CD4+、CD8+T细胞的浸润以及FOXP3+/CD8+、FOXP3+/CD4+与胃癌患者预后没有显著关系。
结论：胃癌肿瘤组织中FOXP3+ T细胞等3种TILs明显高于正常胃组织,其中FOXP3+ T细胞浸润增多升高提示患者预后较差。直接清除FOXP3+ T细胞或抑制FOXP3+ T细胞的功能,可能会延长胃癌术后生存。
Purpose
The aim of the present study was to investigate the expression and the prognostic value of tumor-infiltrated lymphocytes (TILs), especially the prognostic value of Foxp3+ regulatory T cells (Tregs) in gastric cancer patients after radical resection.
Patients and Methods
From 135 patients, who underwent R0 resections with extended lymph nodes dissection (D2) between 1999 and 2005 at Zhongshan Hospital of Fudan Uniersity, CD4+, CD8+ and Foxp3+ TILs were assessed by immunohistochemistry in tissue microarrays and N1 regional lymph nodes sections containing gastric cancer. Prognostic effects of low or high-density TIL subsets were evaluated by Cox regression and Kaplan-Meier analysis using median values as cutoff.
Results
The frequency of CD4+, CD8+ or FOXP3+ TILs in tumor sites was significantly higher than that in normal tissues (Wilcoxon Test, p<0.01). It was found that CD4+, CD8+ TILs FOXP3+/CD8+ ratio and FOXP3+/CD4+ ratio were not associated with overall survival (OS). In the tumor sites, high Tregs density was an independent factor for worse OS (Multivariate analysis HR 2.598,p=0.004). One-year, two-year, three-year and four-year OS rates were 82.6%,65.2%,60.4% and 55.6% for the group with intratumoral high Tregs density, compared with 83.3%,81.8%,77.3% and 77.3% for the group with intratumoral low density (Logrank-test p=0.009). Although the infiltration of Foxp3+ Tregs in N1 regional lymph nodes was associated with lymph nodes metastasis (p=0.043), it wasn't associated with prognosis (Logrank-test p=0.257).
Conclusions
Intratumoral high Foxp3+ Tregs density was an independent predictor for the prognosis of gastric cancer. It can be inferred that deletion of Tregs may be an effective immunotherapy to prolong survival after surgery.
材料与方法：将135例于1999-2005期间在复旦大学附属中山医院行D2根治术胃癌患者的肿瘤组织和正常胃组织制成组织芯片,N1站淋巴结制成病理切片,利用免疫组化的方法,观察不同组织中CD4+、CD8+和FOXP3+ T细胞的浸润情况。利用中位值分组,应用多种统计学方法分析以上3种淋巴细胞与胃癌临床病理特点及患者D2根治术后生存之间的关系。
结果：胃癌肿瘤组织中FOXP3+ T细胞等3种TILs数目明显高于正常组织(配对差值非参检验,p值均小于0.01)；肿瘤内FOXP3+ T细胞浸润多的患者预后较差(Cox多因素生存分析HR=2.598,p=0.004),FOXP3+ T细胞浸润多的患者一年、两年、三年和四年生存率分别是82.6%、65.2%、60.4%和55.6%,而FOXP3+T细胞浸润少的患者一年、两年、三年和四年的生存率分别是83.3%、81.8%、77.3%和77.3%(Logrank检验p=0.009)；淋巴结内FOXP3+ T细胞的浸润数目与淋巴结转移负相关(卡方检验,p=0.043),但对预后无明显影响(Logrank检验p=0.257)。肿瘤内、肿瘤旁和淋巴结内CD4+、CD8+T细胞的浸润以及FOXP3+/CD8+、FOXP3+/CD4+与胃癌患者预后没有显著关系。
结论：胃癌肿瘤组织中FOXP3+ T细胞等3种TILs明显高于正常胃组织,其中FOXP3+ T细胞浸润增多升高提示患者预后较差。直接清除FOXP3+ T细胞或抑制FOXP3+ T细胞的功能,可能会延长胃癌术后生存。
Purpose
The aim of the present study was to investigate the expression and the prognostic value of tumor-infiltrated lymphocytes (TILs), especially the prognostic value of Foxp3+ regulatory T cells (Tregs) in gastric cancer patients after radical resection.
Patients and Methods
From 135 patients, who underwent R0 resections with extended lymph nodes dissection (D2) between 1999 and 2005 at Zhongshan Hospital of Fudan Uniersity, CD4+, CD8+ and Foxp3+ TILs were assessed by immunohistochemistry in tissue microarrays and N1 regional lymph nodes sections containing gastric cancer. Prognostic effects of low or high-density TIL subsets were evaluated by Cox regression and Kaplan-Meier analysis using median values as cutoff.
Results
The frequency of CD4+, CD8+ or FOXP3+ TILs in tumor sites was significantly higher than that in normal tissues (Wilcoxon Test, p<0.01). It was found that CD4+, CD8+ TILs FOXP3+/CD8+ ratio and FOXP3+/CD4+ ratio were not associated with overall survival (OS). In the tumor sites, high Tregs density was an independent factor for worse OS (Multivariate analysis HR 2.598,p=0.004). One-year, two-year, three-year and four-year OS rates were 82.6%,65.2%,60.4% and 55.6% for the group with intratumoral high Tregs density, compared with 83.3%,81.8%,77.3% and 77.3% for the group with intratumoral low density (Logrank-test p=0.009). Although the infiltration of Foxp3+ Tregs in N1 regional lymph nodes was associated with lymph nodes metastasis (p=0.043), it wasn't associated with prognosis (Logrank-test p=0.257).
Conclusions
Intratumoral high Foxp3+ Tregs density was an independent predictor for the prognosis of gastric cancer. It can be inferred that deletion of Tregs may be an effective immunotherapy to prolong survival after surgery.
引文
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