胰腺导管腺癌肿瘤免疫相关的病理学特点及临床意义

Pathological features related to onco-immunity and their clinical significance of pancreatic ductal adenocarcinoma

目的:研究胰腺导管腺癌(PDAC)肿瘤免疫相关的病理学特点及其临床意义。方法:收集中国科学院大学附属肿瘤医院2010年1月至2020年12月192例PDAC患者的病理样本及临床信息,对肿瘤免疫微环境进行形态学评估,免疫组织化学标记肿瘤免疫相关蛋白,结合患者治疗及生存信息,统计分析诸因素之间相互关系及对预后的影响。结果:192例PDAC中,非特殊型腺癌163例(163/192,84.90%),腺鳞癌18例,(18/192,9.37%),其他少见亚型共11例(11/192,5.73%);110例(110/192,57.29%)见神经累犯,86例(86/192,44.79%)见血管侵犯;84例(84/182,46.15%)伴重度慢性炎;52例(52/192,27.08%)肿瘤浸润免疫细胞数量(TII-N)多,60例(60/192,31.25%)主要为淋巴细胞、浆细胞浸润,34例(34/192,17.71%)主要为粒细胞浸润,98例(98/192,51.04%)为混合浸润;缺乏CD3 +T细胞者124例(124/192,66.31%),缺乏CD8 +T细胞者152例(152/192,79.58%);主要组织相容性复合物Ⅰ类分子(MHC-Ⅰ)表达下调156例(156/192,81.25%);PD-L1阳性[综合阳性评分(CPS)≥1]者46例(46/192,23.96%)。统计学分析发现TII-N与脉管瘤栓( P=0.035)、神经累犯( P=0.002)、分期( P=0.004)及长期饮酒( P=0.039)呈显著负相关;免疫细胞种类(TII-T)与胰腺慢性炎呈正相关( P=0.002),与肿瘤分化呈负相关( P=0.024);CD8 +T细胞与CD3 +T细胞( P=0.032)、MHC-Ⅰ表达( P<0.001)、PD-L1表达( P=0.001)呈正相关,与长期吸烟呈负相关( P=0.016)。单因素分析发现组织学非特殊型( P=0.013)、TII-N多( P<0.001)为PDAC的良性预后因素,脉管瘤栓( P=0.032)、神经累犯( P=0.001)、分期晚( P=0.003)及长期饮酒( P=0.004)为其不良预后因素。COX多因素回归分析发现TII-N是PDAC的独立良性因素,而神经累犯为其独立的不良预后风险因素。 结论:PDAC中,TII-N与多种因素相关,它是PDAC独立的良性预后因素;长期饮酒及吸烟可能导致PDAC患者的肿瘤免疫功能受抑。

Objective To investigate the tumor immunity-related pathologic features and clinical significance in pancreatic ductal adenocarcinoma(PDAC).Methods All pathologic materials and clinical information of 192 PDAC patients from the Cancer Hospital of the University of Chinese Academy of Sciences from January 2010 to December 2020 were collected.The onco-immune microenvironment associated morphologic features were evaluated,and MHC-Ⅰ,PD-L1,CD3,and CD8 expression were detected by immunohistochemistry(IHC).Then the correlation between the factors and their influence on prognosis was analyzed.Results There were 163 cases of non-specific adenocarcinoma(163/192,84.90%),18 cases of adeno-squamous carcinoma(18/192,9.37%),and 11 cases of other rare subtypes(11/192,5.73%).Perineural invasion was observed in 110 cases(110/192,57.29%)and vascular invasion in 86 cases(86/192,44.79%).There were 84 cases(84/182,46.15%)with severe chronic inflammation.Tumor infiltrating immune cell numbers(TII-N)were increased in 52 cases(52/192,27.08%).Lymphocytes and plasma cells were the main infiltrating immune cells in 60 cases(60/192,31.25%),whereas in 34 cases(34/192,17.71%)the tumors were mainly infiltrated by granulocytes,and 98 cases(98/192,51.04%)showed mixed infiltration.CD3+T cells were deficient in 124 cases(124/192,66.31%).CD8+T cells were deficient in 152 cases(152/192,79.58%).MHC-Ⅰexpression was down-regulated in 156 cases(156/192,81.25%),and PD-L1 was positive(CPS≥1)in 46 cases(46/192,23.96%).Statistical analysis showed that TII-N was negatively correlated with vascular invasion(P=0.035),perineural invasion(P=0.002),stage(P=0.004)and long-term alcohol consumption(P=0.039).The type of immune cells correlated positively with chronic pancreatic inflammation(P=0.002),and negatively with tumor differentiation(P=0.024).CD8+T cells were positively correlated with CD3+T cells(P=0.032),MHC-Ⅰexpression(P<0.001)and PD-L1 expression(P=0.001),and negatively correlated with long-term smoking(P=0.016).Univariate analysis showed that histological nonspecific type(P=0.013)and TII-N(P<0.001)were the factors for good prognosis.Vascular invasion(P=0.032),perineural invasion(P=0.001),high stage(P=0.003)and long-term alcohol consumption(P=0.004)were adverse prognostic factors.COX multivariate risk analysis found that TII-N was an independent favorable factor for PDAC,while perineural invasion was an independent adverse risk factor.Conclusions TII-N is an independent superior prognostic factor for PDAC,and significantly correlated with many factors;chronic alcohol consumption and smoking may inhibit onco-immunity in PDAC patients.