Department of Radiation Oncology, Guangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, China.
Department of Oncology, Dongguan Songshan Lake Tungwah Hospital, Dongguan, China.
Comput Biol Med. 2024 Sep;180:108937. doi: 10.1016/j.compbiomed.2024.108937. Epub 2024 Jul 28.
Patients with lung cancer exhibit the poorest outcomes when infected with coronavirus disease 2019 (COVID-19). However, the potential impact of COVID-19 on the tumor microenvironment (TME) of lung adenocarcinoma (LUAD) remains unknown.
Expression data and clinical information were sourced from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Prognostic, differentially expressed circadian-related genes (CRGs) were identified using multivariate Cox regression and LASSO regression analyses to establish an immune-related gene signature. The clinical value, immune landscape, somatic mutations, and drug sensitivity of high- and low-risk groups were assessed using Kaplan-Meier curves and immunotherapy cohorts. Finally, in vitro and in vivo experiments were conducted to elucidate the molecular function of melatonin in regulating the immune microenvironment and therapeutic resistance.
Three circadian-related patterns and distinct CRGs clusters were identified based on the abnormal expression of 13 CRGs. Circadian genomic phenotypes were identified based on 13 circadian phenotype-related differentially expressed genes (DEGs). A CRGs risk signature was constructed; the high CRGs risk group displayed an immunosuppressive TME, poor survival, and therapy resistance. Melatonin reversed EGFR-tyrosine kinase inhibitor (EGFR-TKI) resistance by regulating immune cell infiltration into the TME, both in vitro and in vivo.
The investigation revealed crosstalk between CRGs signatures and immune infiltration patterns in LUAD and COVID-19. Melatonin acted as a promising agent to suppress the malignant features of lung cancer and enhance treatment sensitivity by modulating the TME.
患有肺癌的患者在感染 2019 年冠状病毒病（COVID-19）时预后最差。然而，COVID-19 对肺腺癌（LUAD）肿瘤微环境（TME）的潜在影响尚不清楚。
从癌症基因组图谱（TCGA）和基因表达综合数据库（GEO）中获取表达数据和临床信息。使用多变量 Cox 回归和 LASSO 回归分析鉴定预后、差异表达的昼夜节律相关基因（CRGs），以建立免疫相关基因特征。使用 Kaplan-Meier 曲线和免疫治疗队列评估高风险和低风险组的临床价值、免疫景观、体细胞突变和药物敏感性。最后，进行了体外和体内实验，以阐明褪黑素调节免疫微环境和治疗抵抗的分子功能。
基于 13 个 CRGs 的异常表达，确定了三种昼夜节律相关模式和不同的 CRGs 簇。根据 13 个昼夜节律表型相关差异表达基因（DEGs）确定了昼夜节律基因组表型。构建了 CRGs 风险特征；高 CRGs 风险组表现出免疫抑制性 TME、生存不良和治疗抵抗。褪黑素通过调节免疫细胞浸润 TME，在体外和体内均逆转了表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）耐药性。
该研究揭示了 LUAD 和 COVID-19 中 CRGs 特征与免疫浸润模式之间的相互作用。褪黑素通过调节 TME 来抑制肺癌的恶性特征并增强治疗敏感性，是一种很有前途的药物。
