Upregulated YTHDF1 associates with tumor immune microenvironment in head and neck squamous cell carcinomas.
Upregulated YTHDF1 associates with tumor immune microenvironment in head and neck squamous cell carcinomas.
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YTHDF1上调与头颈鳞状细胞癌的肿瘤免疫微环境相关
DOI：
10.21037/tcr-22-503
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发表时间：
2022-11
影响因子：
0.9
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中科院分区：
文献类型：
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背景肿瘤免疫微环境(TME)的性质对头颈部鳞状细胞癌(HNSCC)的发生、预后和免疫治疗的反应至关重要。然而，其基因调控网络仍有待阐明。方法对肿瘤基因组图谱(TCGA)HNSCC患者样本进行计算机筛选，以确定参与调节HNSCC TME的N6-甲基腺苷(M6A)调节剂。分析突变、拷贝数变异(CNV)和转录调控对YTHDF1表达的影响。我们分析了TME的渗透、癌症免疫循环活动以及YTHDF1相关的京都基因和基因组百科全书(KEGG)途径。结果在24个M6A调节因子中，有3个因子(YTHDF1、ELAVL1和METTL3)与TME的侵袭高度相关。作为首选候选基因，YTHDF1在HNSCC中高表达和扩增。YTHDF1启动子获得了活化组蛋白标记和高染色质可及性，这可能是SOX2和TP63转录激活的结果。此外，YTHDF1的表达与HNSCC的恶性表型显著相关，与CD4+T细胞呈正相关，与CD8+T细胞浸润呈负相关。具体地说，YTHDF1的表达与癌症免疫周期和免疫检查点抑制物负相关。在潜在的生物学机制方面，YTHDF1可能与YTHDF2/3相互作用，调节几条重要的免疫相关途径。结论我们鉴定了YTHDF1与TME相关，阐明了HNSCC免疫逃逸的潜在机制，可作为指导免疫治疗的预测指标。
Background The nature of the tumor immune microenvironment (TME) is essential for the head and neck squamous cell carcinomas (HNSCC) initiation, prognosis, and response to immunotherapy. However, its gene regulatory network remains to be elucidated. Methods To identify N6-methyladenosine (m6A) regulators that are involved in regulating the HNSCC TME, a computational screen was applied to The Cancer Genome Atlas (TCGA) HNSCC patient samples. The effects of mutation, copy number variation (CNV), and transcriptional regulation on YTHDF1 expression were analyzed. We analyzed the TME infiltration, cancer-immunity cycle activities, and YTHDF1-related Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Results Among the 24 m6A regulators, 3 factors (YTHDF1, ELAVL1, and METTL3) were highly correlated with TME infiltration. As the top candidate, YTHDF1 was up-regulated and amplified in HNSCC. YTHDF1 promoter gains active histone marks and high chromatin accessibility, which might be transcriptionally activated by SOX2 and TP63. Moreover, YTHDF1 expression significantly associates with tumor malignant phenotype in HNSCC, which has a positive correlation with CD4+ T cells and a negative correlation with CD8+ T cells infiltration. Specifically, YTHDF1 expression is negatively associated with the cancer-immunity cycle and immune checkpoint inhibitors. In terms of the underlying biological mechanisms, YTHDF1 may interact with YTHDF2/3 to regulate several vital immune-related pathways. Conclusions We identify YTHDF1 associated with TME and elucidate an underlying mechanism of immune escape in HNSCC, which might be used as a predictive marker in guiding immunotherapy.