Comparative Analysis and in vitro Experiments of Signatures and Prognostic Value of Immune Checkpoint Genes in Colorectal Cancer.
Comparative Analysis and in vitro Experiments of Signatures and Prognostic Value of Immune Checkpoint Genes in Colorectal Cancer.
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比较分析和体外特征的特征和结直肠癌的免疫检查点基因的预后价值。
DOI：
10.2147/ott.s304297
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发表时间：
2021
影响因子：
4
通讯作者：
Liu Y
中科院分区：
文献类型：
--
作者：
Ma R;Qu X;Che X;Yang B;Li C;Hou K;Guo T;Xiao J;Liu Y
免疫检查点作为癌症免疫逃逸的关键调节因子，可以激发免疫检查点抑制剂（ICI）的出现。本研究的目的是确定免疫检查点基因（ICG）在结直肠癌（CRC）中的表达，并将其单独以及组合表达与CRC的预后和治疗效果相关。从两个公共数据库中收集了47个ICG的RNA表达和CRC患者的临床信息，以阐明这些ICG在CRC中的表达水平和预后价值。然后，使用Shapiro-Wilk正态性检验确定变量的正态性。采用Kaplan-Meier法计算各亚组的总生存率（OS），采用Log rank检验（p < 0.05）确定统计学意义。在癌症基因组图谱（TCGA）和基因表达综合（GEO）队列中，13和9个ICG的表达与CRC预后显著相关。发现一系列ICG与CRC中的TMB、新抗原和MMR显著相关，表明免疫治疗生物标志物和ICG的组合可以实现CRC的准确预后分层，并可能识别可能对检查点抑制剂（CPI）有反应的CRC病例。按CD 48分层的PD 1/PD-L1/IDO 1高表达或低表达亚群与结直肠癌的预后准确相关。此外，体外实验证实VTCN 1（B7-H4）-KD增加抗PD-L1介导的NK细胞对CRC肿瘤细胞的细胞毒性。虽然单个免疫检查点分子的表达不能预测免疫治疗在CRC中的疗效，但我们的研究结果推断，ICG定义的子集与预后相关，并暗示VTCN 1和CD 48可能作为新的免疫靶点。
Immune checkpoints, as pivotal regulators of immune escape in cancer, can motivate the emergence of immune checkpoint inhibitors (ICIs). The aim of this study is to identify the expression of the immune checkpoint genes (ICGs) in colorectal cancer (CRC) and to relate their individual as well as combined expression to prognosis and therapeutic effectiveness in CRC. RNA expression of 47 ICGs and clinical information of CRC patients were collected from two public databases to elucidate the expression levels and prognostic values of these ICGs in CRC. Then, the Shapiro–Wilk normality test was used to determine the normality of variables. Overall survival (OS) rates of each subset were found by Kaplan–Meier method, and the statistical significance was determined by the Log rank test (p < 0.05). The expression of 13 and 9 ICGs was significantly associated with CRC prognosis in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) cohorts. A series of ICGs was found to be significantly associated with TMB, neoantigens and MMR in CRC indicating that the combination of immunotherapy treatment biomarkers and ICGs may achieve accurate prognostic stratification of CRC, and potentially identify CRC cases that might respond to checkpoint inhibitors (CPIs). The subsets of high or low PD1/PD-L1/IDO1 expression stratified by CD48 were accurately associated with prognosis in CRC. In addition, in vitro experiments confirmed that VTCN1(B7-H4)-KD increases anti-PD-L1-mediated NK cell cytotoxicity on CRC tumor cells. Although the expression of a single immune-checkpoint molecule does not predict the efficacy of immunotherapy in CRC, our findings infer that subsets defined by ICGs are associated with prognosis and imply the possibility that VTCN1 and CD48 serve as new immunotherapeutic targets.