肌层浸润性膀胱癌TILs表达及其临床意义TCGA数据库分析

Profiles of tumor infiltrating lymphocytes in muscle-invasive bladder cancer and their clinical significant:A study base on TCGA

目的肿瘤浸润淋巴细胞(tumor infiltrating lymphocytes,TILs)在乳腺癌、黑色素瘤等肿瘤中高表达常常具有较好的生存预后,但TILs在肌层浸润性膀胱癌(muscle-invasive bladder cancer,MIBC)的表达及其对MIBC患者预后影响尚不清楚。本研究通过癌症和肿瘤基因图谱(The Cancer Genome Atlas,TCGA)的大规模基因组测序所得结果分析TILs在MIBC组织中的表达及其临床意义。方法通过TCGA V15.0数据库筛选并下载412例膀胱癌患者数据资料(自2006年建库起至2019-02-20),经过R语言中相关的程序包及CIBERSORT软件分析TIls在膀胱肿瘤组织及癌旁组织的表达,并结合临床数据分析TILs的不同表达量在MIBC的预后作用。结果整体分析可得CD8T细胞与活化的记忆CD4T正相关性最强,但与未活化的CD4T负相关(r值分别为0.57和-0.55);未活化肥大细胞(P=0.002)、原始B细胞(P=0.006)、记忆B细胞(P=0.036)在正常组织中含量较高,而巨噬细胞M0(P=0.006)、巨噬细胞M1(P=0.009)、未活化自然杀伤NK细胞(P=0.033)在肿瘤组织中含量较高,411例膀胱癌患者(剔除未报道生存状态1例)中有≥3年吸烟史(χ^2=27.4,P<0.001)和组织学分级高级别(χ^2=7.14,P=008)死亡率高,放射治疗未能使膀胱癌患者明显获益(χ^2=4.76,P=0.03);在404例MIBC患者中,癌组织中高含量的CD8T细胞(P=0.016)及活化记忆CD4T细胞(P=0.023)比低含量者生存时间更长,未活化的CD4T细胞(P=0.021)及巨噬细胞M0低含量(P=0.024)比高含量者预后更佳;CD8T细胞在男性中含量更高(P=0.007);巨噬细胞M0在临床分期越高其含量越高(P=0.032)。结论数据分析表明,TILs的不同细胞含量在膀胱癌中差异表达,这些差异性可能是膀胱癌患者预后和治疗反应的重要决定因素;另外,对肿瘤细胞免疫反应的详细分析有助于提高临床预测和确定免疫治疗的候选药物。

OBJECTIVE Previous studies suggested that Tumor infiltrating lymphocytes(TILs)have high survival prognosis in breast cancer,melanoma and other tumors.However,the expression prifile of TILs and its role inMuscle-invasive Bladder Cancer(MIBC)remain unclear.This study aimed to analyse expression of TILs and its clinical significance in patients with MIBC.METHODS By the R package and CIBERSORT software,the expression and prognostic of TILs in MIBC tumor tissues and non-tumor tissues were analyzed in publicly available databases the Cancer Genome Atlas(TCGA,From 2006 to 2019-02-20,version:V15.0).RESULTS In TCGA database,T cells CD8 had the strongest positive correlation with T cells CD 4 memory activated,but are most negatively correlated with unactivated CD4 T(correlation coefficients 0.57,-0.55,respectively);Mast cells resting(P=0.002),B cells naive(P=0.006)and B cells memory(P=0.036)were high content in normal tissues,macrophages M0(P=0.006),macrophage M1(P=0.009),and NK cells resting(P=0.033)high content in tumor tissues;411 patients with bladder cancer had a history of smoking for many years(χ^2=27.4,Pvalue<0.001),the higher the pathological grade,the higher the mortality(χ^2=7.14,P=008),radiation Treatment failed to significantly benefit patients with bladder cancer(χ^2=4.76,P=0.03);in 407 MIBC,high content of T cells CD8(P=0.016)and T cells CD4 memory activated(P=0.023)had longer survival time than low expression,T cells CD4 resting(P=0.021)and low content of macrophage M0(P=0.024)had a better prognosis than those with high content;T cells CD8 high content in males(P=0.007);the higher the clinical stage of macrophage M0,the more content(P=0.032).CONCLUSIONS Data analysis showed that different components of tumor infiltrating lymphatics were differentially content in bladder cancer.These differences may be important determinants of prognosis and treatment response in bladder cancer patients.In addition,detailed analysis of immune responses to tumor cells may help to improve clinical prediction and determination of drug candidates for immunotherapy.