胰腺癌免疫微环境组织驻留CD103^(+)CD8^(+)T细胞浸润分布及其临床意义

Infiltration of tissue-resident CD103+CD8+T cells in the tumor microenvironment of pancreatic cancer and its clinical significance

目的探讨胰腺癌肿瘤免疫微环境中组织驻留CD103^(+)CD8^(+)T细胞的分布及浸润程度,分析其临床意义。方法应用多色免疫荧光染色检测胰腺癌组织芯片(HPanA120Su02,上海芯超生物科技有限公司)中CD103^(+)CD8^(+)T细胞的浸润程度及其临床相关性。共53例胰腺癌组织(2009-01-06-2013-08-07行手术治疗且经病理确诊的初诊胰腺癌患者)和54例癌旁正常组织纳入研究。通过组织芯片中PD-L1表达阳性比例,取Cutoff为10%,以PD-L1<10%为PD-L1低表达组,PD-L1≥10%为PD-L1高表达组,进一步分析不同亚组中的CD103^(+)CD8^(+)T细胞的浸润程度对预后的影响。结果胰腺癌组织中CD103^(+)CD8^(+)T细胞浸润程度〔20.9个/mm^(2)(4.8~46.3)〕较正常组织〔0.8个/mm^(2)(0~2.8)〕增高,差异有统计学意义,P<0.001。CD8^(+)T细胞中CD103^(+)CD8^(+)T所占比例为21.6%(10.5%~39.8%),较正常组织〔0.6%(0~3.1%)〕增高,P<0.001。PD-L1高表达组患者CD103^(+)CD8^(+)T细胞〔37.9个/mm^(2)(20.1~102.7)〕浸润程度较PD-L1低表达组患者〔8.5个/mm^(2)(3.1~26.8)〕增高,差异有统计学意义,P=0.014。CD8^(+)T和CD103^(+)CD8^(+)T细胞浸润程度均与PD-L1阳性表达水平呈正相关(r=0.354,P=0.009;r=0.555,P<0.001)。PD-L1高表达患者总生存(OS)差于PD-L1低表达患者(HR=2.154,95%CI为1.158~4.000,P=0.001)。CD8^(+)T和CD103^(+)CD8^(+)T细胞浸润程度高低均与OS无统计学意义的关联,均P>0.05。PD-L1高表达的患者较PD-L1低表达患者有更高的死亡风险(HR=2.732,95%CI为1.431~5.216,P=0.002)。多因素Cox分析显示,PD-L1表达水平可作为胰腺癌患者预后评估的独立风险因素(HR=4.066,95%CI为1.539~10.743,P=0.005)。PD-L1高表达+CD8^(+)T细胞高浸润组患者OS差于PD-L1低表达+CD8^(+)T细胞高浸润组(HR=6.429,95%CI为1.608~25.700,P=0.027)。PD-L1高表达+CD103^(+)CD8^(+)T细胞高浸润组患者OS差于PD-L1低表达+CD103^(+)CD8^(+)T细胞低浸润组(HR=1.600,95%CI为0.777~3.294,P=0.018)。结论CD103^(+)CD8^(+)T细胞在胰腺癌组织和PD-L1高表达患者中高度浸润,PD-L1高表达合并CD103^(+)CD8^(+)T细胞高度浸润患者对于免疫治疗可能具有更高的治疗反应率。

Objective To investigate the infiltration density and prognostic significance of tissue-resident CD103^(+)CD8^(+)T cells in pancreatic cancer patients.Methods Multiplex immunohistochemistry(mIHC)was used to detect the infiltration density of CD103^(+)CD8^(+)T cells in pancreatic cancer tissue microarray(HPanA120Su02)and its clinical significance was analyzed.A total of 53cases of pancreatic cancer tissue(patients with pancreatic cancer diagnosed pathologically from January 6,2009to August 7,2013)and 54cases of normal adjacent tissues were included in the study.The Cutoff of the positive proportion of PD-L1expression was 10%.PD-L1<10%was the low expression group of PD-L1,and PD-L1≥10%was the high expression group of PD-L1.The prognosis value of the infiltration degree of CD103^(+)CD8^(+)T cells in different subgroups was further analyzed.Results The infiltrating density of CD103^(+)CD8^(+)T cells[20.9(4.8-46.3)]in pancreatic cancer tissues was significantly higher than that in normal tissues[0.8(0-2.8)],P<0.001.The proportion of CD103^(+)CD8^(+)T in CD8^(+)T cells[21.6%(10.5%-39.8%)]was significantly higher than that in normal tissues[0.6%(0-3.1%)].The infiltration density of CD103^(+)CD8^(+)T cells[37.9(20.1-102.7)]in the PD-L1high expression group was higher than that in the PD-L1low expression group[8.5(3.1-26.8)],P=0.014.The infiltrating density of CD8^(+)T cells and CD103^(+)CD8^(+)T cells were correlated with the expression levels of PD-L1(r=0.354,P=0.009;r=0.555,P<0.001).The OS of patients with high PD-L1expression was worse than that of patients with low PD-L1expression(HR=2.154,95%CI=1.158-4.000,P=0.001).The infiltrating357.5 density of CD103^(+)cells,CD8^(+)T cells and CD103^(+)CD8^(+)T cells was not significantly correlated with the OS(P>0.05).Patients with high PD-L1expression had poorer prognosis than patients with low PD-L1expression(HR=2.732,95%CI:1.431-5.216,P=0.002).Multivariate Cox model analysis showed that PD-L1expression level could be used as an independent risk factor for the prognosis of pancreatic cancer patients(HR=4.066,95%CI:1.539-10.743,P=0.005).The OS of patients in the PD-L1high+CD8^(+)Thigh was worse than that of PD-L1low+CD8^(+)Thigh group(HR=6.429,95%CI:1.608-25.700,P=0.027).The OS of the patients in the PD-L1high+CD103^(+)CD8^(+)Thigh group was worse than that of the PD-L1low+CD103^(+)CD8^(+)Tlowgroup(HR=1.600,95%CI:0.777-3.294,P=0.018).Conclusion CD103^(+)CD8^(+)T cells are highly infiltrated in pancreatic cancer tissues and patients with high PD-L1expression.Patients with high PD-L1expression and high infiltration densities of CD103^(+)CD8^(+)T cells may have higher response rates to immunotherapy.