Li Depei, Hu Wanming, Lin Xiaoping, Zhang Ji, He Zhenqiang, Zhong Sheng, Wen Xia, Zhang Peiyu, Jiang Xiaobing, Duan Hao, Guo Chengcheng, Wang Jian, Zeng Jing, Chen Zhongping, Mou Yonggao, Sai Ke
Department of Neurosurgery/Neuro-oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
Front Cell Dev Biol. 2021 Mar 19;9:653240. doi: 10.3389/fcell.2021.653240. eCollection 2021.
Proteins containing the caspase recruitment domain (CARD) play critical roles in cell apoptosis and immunity. However, the impact of CARD genes in tumor immune cell infiltration, responsiveness to checkpoint immunotherapy, and clinical outcomes of gliomas remains unclear. Here, we explore using CARD genes to depict the immune microenvironment and predict the responsiveness of gliomas to anti-PD-1 therapy.
The genome and transcriptome data of 231 patients with isocitrate dehydrogenase wild-type (IDH-wt) gliomas were retrieved from The Cancer Genome Atlas (TCGA) database to screen CARD genes associated with T lymphocyte infiltration in gliomas. Weighted co-expression network and LASSO penalized regression were employed to generate a CARD-associated risk score (CARS). Two independent and publicly available datasets were used to validate the effectiveness of CARS.
The CARS divided the 231 glioma patients into high- and low-risk subgroups with distinct immune microenvironment and molecular features. The high-risk group had high CARS and was characterized by enrichment of dysfunctional T lymphocytes in a profound immunosuppressive microenvironment, whereas the low-risk group had low CARS and exhibited an immune exclusion genotype. Moreover, signaling aberrations including upregulation of PI3K/Akt/mTOR, NF-κB, and TGF-β were found in the high-risk group. In contrast, the activated WNT pathway was more evident in the low-risk group. Furthermore, we found that an elevated CARS indicated a decreased overall survival for IDH-wt gliomas under standard care but a clinical benefit from checkpoint immunotherapy.
This study developed an immune- and prognosis-relevant risk score, which could be used to enhance our understanding of the heterogeneity of immune microenvironment of gliomas and facilitate to identify patients who will benefit from checkpoint immunotherapy.
含有半胱天冬酶招募结构域（CARD）的蛋白质在细胞凋亡和免疫中发挥关键作用。然而，CARD基因在肿瘤免疫细胞浸润、对检查点免疫疗法的反应以及胶质瘤临床结局中的影响仍不明确。在此，我们探索利用CARD基因描绘免疫微环境并预测胶质瘤对抗程序性死亡蛋白1（PD-1）治疗的反应性。
从癌症基因组图谱（TCGA）数据库检索231例异柠檬酸脱氢酶野生型（IDH-wt）胶质瘤患者的基因组和转录组数据，以筛选与胶质瘤中T淋巴细胞浸润相关的CARD基因。采用加权共表达网络和套索罚回归生成与CARD相关的风险评分（CARS）。使用两个独立的公开可用数据集验证CARS的有效性。
CARS将231例胶质瘤患者分为高风险和低风险亚组，这两个亚组具有不同的免疫微环境和分子特征。高风险组CARS高，其特征是在深度免疫抑制微环境中功能失调的T淋巴细胞富集，而低风险组CARS低，表现出免疫排斥基因型。此外，在高风险组中发现包括磷脂酰肌醇-3-激酶/蛋白激酶B/哺乳动物雷帕霉素靶蛋白（PI3K/Akt/mTOR）、核因子κB（NF-κB）和转化生长因子-β（TGF-β）上调在内的信号异常。相比之下，活化的WNT信号通路在低风险组中更明显。此外，我们发现CARS升高表明IDH-wt胶质瘤在标准治疗下总生存期缩短，但从检查点免疫疗法中可获得临床益处。
本研究开发了一种与免疫和预后相关的风险评分，可用于加深我们对胶质瘤免疫微环境异质性的理解，并有助于识别将从检查点免疫疗法中获益的患者。
