CD8^(+)T细胞癌巢/间质比对早期非小细胞肺癌隐匿性淋巴结转移的影响  

Effect of tumor CD8^(+)T/stroma ratio on occult lymph node metastasis in early-stage non-small cell lung cancer

作　　者：李超卓 景洪标 胡梦钰 杨丽颖 孙晓蓉 邢力刚 LI Chaozhuo;JING Hongbiao;HU Mengyu;YANG Liying;SUN Xiaorong;XING Ligang(School of Clinical Medicine,Shandong Second Medical University,Weifang,Shandong 261053,China;Shandong Cancer Hospital and Institute,Shandong First Medical University and Shandong Academy of Medical Sciences,Jinan,Shandong 250117,China;Department of Graduate,Shandong First Medical University(Shandong Academy of Medical Sciences),Jinan,Shandong 250117,China;Cheeloo College of Medicine,Shandong University,Jinan,Shandong 250012,China)

机构地区：[1]山东第二医科大学临床医学院,山东潍坊261053 [2]山东省肿瘤防治研究院(山东省肿瘤医院病理科),山东第一医科大学(山东省医学科学院),山东济南250117 [3]山东省肿瘤防治研究院(山东省肿瘤医院核医学科),山东第一医科大学(山东省医学科学院),山东济南250117 [4]山东省肿瘤防治研究院(山东省肿瘤医院放疗科),山东第一医科大学(山东省医学科学院),山东济南250117 [5]山东第一医科大学(山东省医学科学院)研究生部,山东济南250117 [6]山东大学齐鲁医学院,山东济南250012

出　　处：《中华肿瘤防治杂志》2024年第12期731-737,758,共8页Chinese Journal of Cancer Prevention and Treatment

基　　金：国家自然科学基金(82172866,82373424);山东省自然科学基金(ZR2021LZL005);山东省科学技术厅纵向项目(2021CXGC011102)。

摘　　要：目的 分析临床早期非小细胞肺癌(NSCLC)患者肿瘤原发灶的肿瘤中心(TC)和侵袭性边缘(IM,包括癌巢和间质)的CD8^(+) T细胞和程序性死亡受体-1(PD-1)^(+) CD8 T细胞的浸润水平,并探究其与隐匿性淋巴结转移(OLNM)的关系。方法 回顾性收集2014-01-01-2021-12-31在山东省肿瘤医院接受根治性手术的154例临床早期NSCLC患者的术后组织标本,构建组织芯片(TMA),并进行多重免疫荧光染色以评估TC和IM的CD8及PD-1^(+) CD8的密度。曼-惠特尼U检验分析NSCLC伴OLNM和无OLNM患者的CD8和PD-1^(+) CD8浸润差异。使用中位数将患者分为高/低密度组,二元logistic回归分析OLNM发生的影响因素。结果 在临床早期NSCLC的TC和IM上,CD8分别占所有细胞的4.6%和5.6%,PD-1^(+) CD8分别占CD8的9.1%和6.9%。临床早期NSCLC患者发生OLNM时,IM的总CD8及间质CD8浸润增加(cN^(-)pN^(+)vs cN^(-)pN^(-), 63.78 vs 43.87,Z=2.995,P=0.003;93.57 vs 60.84,Z=2.631,P=0.009),同时TC间质和IM癌巢中的PD-1^(+) CD8/CD8比例降低(cN^(-)pN^(+)vs cN^(-)pN^(-), 7.5%vs 10.2%,Z=-2.227,P=0.026;4.4%vs 8.4%,Z=-2.093,P=0.036)。多因素logistic回归分析显示,TC的癌巢CD8/间质CD8比例降低是早期NSCLC发生OLNM的独立危险因素(OR=2.339, 95%CI:1.201~4.556,P=0.012)。结论 TC的癌巢CD8/间质CD8比降低,CD8向癌巢内浸润减少,与早期NSCLC的OLNM发生有关,同时TC间质和IM癌巢中的CD8表面PD-1表达降低。Objective To analyze infiltration levels of CD8^(+)T cells and programmed death 1(PD-1)+CD8 T cells in the tumor center(TC)and invasive margin(IM,including the tumor and stroma area)of primary tumors in clinical early-stage non-small cell lung cancer(NSCLC),and to explore the relationship between occult lymph node metastasis(OLNM)and immune cells.Methods Postoperative tissue specimens were retrospectively collected from 154 patients with clinical early-stage NSCLC who underwent radical surgery in Shandong Cancer Hospital from January 1,2014 to December 31,2021 to construct tissue microarray(TMA).Multiple immunofluorescence staining was performed to evalu-ate the density of CD8 and PD-1^(+)CD8 in TC and IM.The infiltration differences of CD8 and PD-1^(+)CD8 between pa-tients with OLNM and without OLNM were analyzed by using the Mann-Whitney U test.Patients were divided into high and low density groups by median value,and binary logistic regression was carried out to analyze factors influen-cing the occurrence of OLNM.Results In the regions of TC and IM in clinical early-stage NSCLC,CD8 accounted for 4.6%and 5.6%of all cells,and PD-1^(+)CD8 accounted for 9.1%and 6.9%of CD8,respectively.In the development of OLNM in clinical early-stage NSCLC,the infiltration of total CD8 and stroma CD8 increased in IM(cN^(-)pN^(+)vs cN^(-)pN^(-),63.78 vs 43.87,Z=2.995,P=0.003;93.57 vs 60.84,Z=2.631,P=0.009).NSCLC patients with OLNM had a lower proportion of PD-1^(+)CD8/CD8 than patients without OLNM both in the stroma of TC and tumor of IM(cN^(-)pN^(+)vs cN^(-)pN^(-),7.5%vs 10.2%,Z=-2.227,P=0.026;4.4%vs 8.4%,Z=-2.093,P=0.036).The multivariate lo-gistic regression analyses demonstrated that the tumor CD8/stroma CD8 ratio decrease in TC was the independent risk factor of the occurrence of OLNM in early-stage NSCLC(OR=2.339,95%CI:1.201-4.556,P=0.012).Conclusions The decrease in tumor CD8/stroma CD8 ratio in the TC with reduced infiltration of CD8 into cancer nests,is associated with the occurrence of OLNM in early-stage NSCLC.The decr

关 键 词：非小细胞肺癌 隐匿性淋巴结转移 肿瘤免疫微环境 CD8 程序性死亡受体-1 

分 类 号：R734.2[医药卫生—肿瘤]