【摘要】 目的 探讨肾透明细胞癌(ccRCC)组织中乳酸脱氢酶D(LDHD)的表达与其临床病理特点和预后的关系，并分析LDHD表达与免疫细胞浸润及免疫检查点(ICPs)的关系。方法 收集2011-01-01-2018-12-31滨州医学院附属医院确诊的71例ccRCC患者临床资料及组织标本，利用免疫组织化学法检测LDHD在ccRCC肿瘤组织和癌旁正常组织中的表达情况，分析其临床意义。采用肿瘤免疫估计资源(TIMER)和基于基因表达水平值的交互式分析平台(GEPIA)数据库分析LDHD与免疫细胞浸润和ICPs的关系。结果 LDHD蛋白在肾小球组织不表达，在近曲小管、髓袢(近直小管、细段、远直小管)、远曲小管和集合管组织强表达呈递减趋势。与癌旁正常肾组织相比，ccRCC中LDHD蛋白表达水平下调，P<0.001。Cox风险回归分析表明LDHD (HR=0.310,95%CI:0.102～0.939,P=0.038)、肿瘤最大径(HR=1.349,95%CI:1.067～1.705,P=0.012)、国际泌尿病理学会分级(HR=2.473,95%CI:1.005～6.086,P=0.049)和T分期(HR=0.517,95%CI:0.268～0.995,P=0.048)是ccRCC患者的独立预后因素。TIMER数据库分析显示，LDHD转录本每百万读数(TPM)的对数与肿瘤纯度呈正相关(r_s=0.242,P<0.001),与B细胞(r_s=-0.120,P=0.010)、CD4~+T细胞(r_s=-0.143,P=0.002)、CD8~+T细胞(r_s=-0.131,P=0.006)、巨噬细胞(r_s=-0.101,P=0.033)、中性粒细胞(r_s=-0.155,P<0.001)和树突状细胞(r_s=-0.158,P<0.001)呈负相关。TIMER和GEPIA数据库结果显示LDHD的TPM对数与PD-1的TPM对数(r_s=-0.220,P<0.001;r=-0.180,P<0.001)和CTLA-4的TPM对数(r_s=-0.253,P<0.001;r=-0.260,P<0.001)呈负相关。结论 LDHD在ccRCC中低表达，与PD-1和CTLA-4呈负相关，提示LDHD可能介导ccRCC的免疫逃逸，LDHD可能是ccRCC免疫治疗的靶点。更多还原

【Abstract】 Objective To investigate the relationship between the expression of lactate dehydrogenase D(LDHD) and its clinicopathological features and prognosis in clear cell renal cell carcinoma(ccRCC), and to analyze the correlation between the expression of LDHD and immune cell infiltration, immune checkpoints(ICPs). Methods We collected the clinical data and tissue specimens of 71 ccRCC patients diagnosed in the Affiliated Hospital of Binzhou Medical College from 2011-01-01-2018-12-31 and detected the expression of LDHD in normal kidney adjacent to tumor and ccRCC tumor tissue by immunohistochemistry. The expression of LDHD in normal kidney adjacent to tumor and ccRCC tumor tissue and its clinicopathological significance were analyzed. Tumor Immune Estimation Resource(TIMER) and Gene Expression Profiling Interactive Analysis(GEPIA) databases were used to investigate the correlation of LDHD with immune cell infiltration and ICPs.Results LDHD protein was not expressed in glomeruli,but there was a decreasing trend in the proportion of LDHD strongly expressed in proximal convoluted tubules,myeloid loops(proximal straight tubules,thin segments,distal straight tubules),distal convoluted tubules and collecting tuducts.Compared with paracancer normal renal tissue,the expression level of LDHD protein in ccRCC was down-regulated(P<0.001).Cox risk regression analysis indicated that LDHD(HR=0.310,95%CI:0.102-0.939,P=0.038),maximum tumor diameter(HR=1.349,95%CI:1.067-1.705,P=0.012),International Society of Urological Pathology grade(HR=2.473,95%CI:1.005-6.086,P=0.049),and T stage(HR=0.517,95%CI:0.268-0.995,P=0.048)were independent prognostic factors for ccRCC patients.The analysis of TIMER database showed that the logarithm of transcripts per kilobase million(TPM)of LDHD was significantly positively correlated with tumor purity(r_s=0.242,P<0.001),and negatively correlated with B cells(r_s=-0.120,P=0.010),CD4~+T cells(r_s=-0.143,P=0.002),CD8~+T cells(r_s=-0.131,P=0.006),macrophages(r_s=-0.101,P=0.033),neutrophils(r_s=-0.155,P<0.001),and dendritic cells(r_s=-0.158,P<0.001).The results of TIMER and GEPIA database showed that the logarithm of TPM of LDHD and that of PD-1(r_s=-0.220,P<0.001;r=-0.180,P<0.001)and the logarithm of TPM of CTLA-4(r_s=-0.253,P<0.001;r=-0.260,P<0.001)showed a negative correlation.Conclusion The expression of LDHD is low in ccRCC and negatively correlated with PD-1and CTLA-4,suggesting that LDHD may mediate the immune escape of ccRCC,and LDHD may be the target of ccRCC immunotherapy.更多还原