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胰腺癌免疫微环境对临床病理特征及预后的影响

Prognostic value of tumor infiltration immune cells in pancreatic cancer

摘要:

目的 探讨免疫细胞CD8+T细胞、调节性T细胞(Treg)和骨髓来源的抑制细胞(MDSC)对胰腺癌患者预后的影响.方法 回顾性收集天津医科大学肿瘤医院2010年1月至2012年5月收治的80例胰腺癌患者的肿瘤组织标本,对CD8、FOXP3和CD33进行免疫组化染色并进行评分,记录患者临床病理学资料并对生存期进行随访,随访截至2015年1月.采用Kaplan-Meier、Log-rank检验及COX回归多因素分析肿瘤浸润的各群免疫细胞对预后的影响,采用x2检验分析各群免疫细胞浸润水平与临床病理学特征的相关性.建立小鼠皮下成瘤模型,给予Treg及MDSC清除治疗,绘制肿瘤生长曲线,通过t检验比较治疗前后肿瘤体积变化、Ki-67+细胞比例及肿瘤浸润CD8+T细胞比例的变化.结果 本组80例患者均获得随访,随访率为100%,中位随访时间为33.2个月(7.4~59.9个月).胰腺癌浸润CD8+T细胞高浸润组生存期[(21.6±1 1.9)个月]长于低浸润组[(13.6±7.4)个月] (x2=4.647,P=0.031).与Treg高浸润组[(13.4±8.8)个月和(9.5±8.8)个月]相比,Treg低浸润组患者的总体生存时间[(20.9±8.5)个月]和无复发生存时间[(15.2±9.0)个月]长(x2=10.528、6.288,P=0.001、0.012),且Treg高浸润组的肿瘤体积较大(x2=4.073,r=0.226,P=0.044).与MDSC高浸润组[(13.8±7.6)个月和(10.2±7.5)个月]相比,MDSC低浸润组的总体生存时间[(23.5±11.8)个月]和无复发生存时间[(17.9±11.3)个月]长(x2=5.724、7.430,P=0.017、0.006),且MDSC高浸润组患者更容易出现淋巴结转移(x2=4.714,r=0.243,P=0.030).COX回归多因素分析结果显示,pTNM分期(P=0.008)、MDSC(P=0.034)、Treg(P=0.009)是胰腺癌患者总体生存率的独立预后因素;pTNM分期(P=0.003)和MDSC(P=0.018)是胰腺癌患者无复发生存率的独立预后因素.动物实验结果表明,Treg联合MDSC清除治疗可使肿瘤体积明显减小[(1 396.3±442.5)cm3比(3 356.9±533.5) mm3](=4.986,P=0.018);治疗组Ki-67+细胞比例(23%±5%)较对照组(55%±10%)低(t=3.130,P=0.011),治疗组CD8+T细胞水平(3.25%±0.69%)较对照组(0.76%±0.25%)高(t=3.393,P=0.007).结论 MDSC和Treg浸润水平及pTNM分期为胰腺癌的独立预后因素.清除Treg和MDSC治疗能够抑制肿瘤生长并提高肿瘤CD8+T细胞的浸润水平.

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abstracts:

Objective To investigate the prognostic effect of tumour-infihrating immune cell,including CD8+T cell,regulatory T-cell (Treg) and myeloid-derived suppressor cells (MDSC) on pancreatic patients.Methods This study retrospectively collected the data of 80 patients who were histologically diagnosed of pancreatic cancer and underwent classical R0 surgical resection at Tianjin Medical University Cancer Institute and Hospital from January 2010 to May 2012.All patients survival were followed up until the cut-off date of January 2015.Clinicopathological features including immunohistochemical staining of FOXP3,CD8 and CD33 were reviewed as indice for evaluating the prognosis of pancreatic patients.The prognostic effect of tumour-infiltrating immune cells were analysed by Kaplan-Meier and Log-rank test.Multiple-factor analysis was conducted with the Cox regression model.The correlation between tumourinfiltrating immune cells and clinicopathological features was analysed by x2 test.The C57BL/6 mouse model was used to evaluate the efficacy of Treg and MDSC depletion therapy in vivo.Student's t-test was applied to assess the difference of the tumour volume,Ki-67 positive rate and CD8+ T-cell infiltration proportion between depletion group and control group.Results Eventually,80 patients were included and no patient was lost during the follow-up period.The median follow-up time was 33.2 months (7.4-59.9 months).Patients with high level of tumour-infiltrating CD8+T cells had longer overall survival (OS) time ((21.6±11.9)months vs.(13.6±7.4) months,x2 =4.647,P =0.031) than those with low level of tumour-infiltrating CD8+T cells.Tumor infiltration FOXP3+ cells were strongly associated with reduced OS ((20.9±8.5) months vs.(13.4 ± 8.8) months,x2 =10.528,P =0.001),reduced relapse free survival (RFS) ((15.2±9.0) months vs.(9.5± 8.8) months,x2 =6.288,P =0.012) and larger tumor size (x2 =4.073,r =0.226,P =0.044).The high intratumoural MDSC group showed a significantly shorter OS ((23.5± 11.8) months vs.(13.8± 7.6) months,x2 =5.724,P =0.017),RFS ((17.9± 11.3) months vs.(10.2± 7.5) months,x2 =7.430,P =0.006) and more advanced N stage (x2 =4.714,r =0.243,P =0.030) than the low intratumoural MDSC group.Multivariate Cox analysis revealed that pTNM (P =0.008),tumourinfiltrating Treg density (P=0.009) and intratumoural MDSC density (P =0.034) were independent and negative prognostic factors for OS;pTNM (P =0.003) and tumour-infiltrating MDSC level(P =0.018) were independent and negative factors for RFS.The experiment in vivo revealed that Treg and MDSC depletion therapy significantly decreased tumour volume in the C57BL/6 mouse model of subcutaneous tumours ((1 396.3±442.5) mm3 vs.(3 356.9± 533.5) mm3,t =4.986,P =0.018).Tumour Ki-67 positive rate significantly decreased (23%±5% vs.55% ± 10%,t =3.130,P =0.011) in Treg and MDSC depletion group,whereas,the proportion of tumour-infiltrating CD8+T cells significantly increased in depletion groups (3.25%±0.69% vs.0.76% ± 0.25%,t =3.393,P =0.007).Conclusions Tumour-infiltrating Treg,MDSC level and pTNM stage are independent prognostic factors for patients with pancreatic cancer.Treg and MDSC depletion therapy can significantly retard tumour growth and increase the level of tumour-infiltrating CD8+ T-cells in the C57BL/6 mouse model of subcutaneous tumours.

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