Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China.
Department of Respiratory Medicine, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China.
J Transl Med. 2024 Aug 22;22(1):781. doi: 10.1186/s12967-024-05530-y.
Naïve CD4 T cells and their differentiated counterparts play a significant regulatory role in the tumor immune microenvironment, yet their effects on lung adenocarcinoma (LUAD) are not fully understood.
We utilized Mendelian randomization to assess the causal association between naïve CD4 T cells and LUAD. Employing a modified single-sample Gene Set Enrichment Analysis (ssGSEA) algorithm with The Cancer Genome Atlas (TCGA) database, we determined the infiltration levels of naïve CD4 T cells and their differentiation subtypes and investigated their correlation with clinical characteristics. Potential regulatory pathways of T helper cells were identified through Mantel tests and Kyoto Encyclopedia of Genes and Genomes (KEGG) database enrichment analysis.
Mendelian randomization analysis revealed an inhibitory effect of naïve CD4 T cells on LUAD (false discovery rate < 0.05), which was corroborated by observational experiments using TCGA database. Specifically, T helper cell type 2 demonstrated a promotive effect on LUAD in terms of overall, disease-free, and progression-free survival (p < 0.05). Moreover, regulatory T cells exhibited a protective effect on LUAD in terms of disease-specific survival (p < 0.01). Concurrently, we explored the overall impact of naïve CD4 T cell differentiation subtypes on LUAD, revealing upregulation in pathways such as neutrophil degranulation, MAPK family signaling pathways, and platelet activation, signaling, and aggregation.
Naïve CD4 T cells and their differentiated counterparts play essential regulatory roles in the tumor immune microenvironment, demonstrating bidirectionality in their effects.Thus, elucidating the mechanisms and developing novel cell differentiation-inducing agents will benefit anti-cancer therapy.
幼稚 CD4 T 细胞及其分化产物在肿瘤免疫微环境中发挥重要的调节作用，但它们对肺腺癌（LUAD）的影响尚未完全阐明。
我们利用孟德尔随机化来评估幼稚 CD4 T 细胞与 LUAD 之间的因果关系。利用经过改良的单样本基因集富集分析（ssGSEA）算法和癌症基因组图谱（TCGA）数据库，我们确定了幼稚 CD4 T 细胞及其分化亚型的浸润水平，并研究了它们与临床特征的相关性。通过 Mantel 检验和京都基因与基因组百科全书（KEGG）数据库富集分析确定了 T 辅助细胞的潜在调节途径。
孟德尔随机化分析显示幼稚 CD4 T 细胞对 LUAD 具有抑制作用（错误发现率<0.05），这一结果得到了 TCGA 数据库的观察性实验的验证。具体而言，辅助性 T 细胞 2 型在 LUAD 的总体、无病和无进展生存方面表现出促进作用（p<0.05）。此外，调节性 T 细胞在 LUAD 的疾病特异性生存方面表现出保护作用（p<0.01）。同时，我们探讨了幼稚 CD4 T 细胞分化亚型对 LUAD 的总体影响，发现其上调了中性粒细胞脱颗粒、MAPK 家族信号通路和血小板激活、信号转导和聚集等途径。
幼稚 CD4 T 细胞及其分化产物在肿瘤免疫微环境中发挥重要的调节作用，其作用具有双向性。因此，阐明其机制并开发新型细胞分化诱导剂将有助于癌症治疗。
