Liu Zheming, Zhu Hengbo, Zhang Fengxia, Huang Wenting, Zhu Shipeng, He Songjiang, Yao Yi, Song Qibin, Zhang Xue
Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China.
Wuhan University Shenzhen Research Institute, Shenzhen, China.
Front Cell Dev Biol. 2025 Mar 24;13:1554705. doi: 10.3389/fcell.2025.1554705. eCollection 2025.
MYD88 (myeloid differentiation primary response 88) is a key adaptor protein mediate immune responses, primarily through Toll-like receptors (TLRs) and interleukin-1 receptor (IL-1R) signaling. The TLR/MYD88 pathway plays a critical role in dendritic cells (DC) maturation and function, contributing to the body's innate immunity. Recent studies have further highlighted MYD88's pivotal role in intrinsic immunity and its regulatory influence on the tumor microenvironment (TME) in hepatocellular carcinoma (HCC). The expression of MYD88 in DCs and its regulatory role in the TME have gained increasing attention.
RNA-sequencing data retrieved from the TCGA and GEO databases were utilized for both the training and validation of our signature. Single-cell RNA transcriptome data from GEO were analyzed to investigate the correlation among subclusters of T cells, myeloid cells, and dendritic cells (DCs) within the HCC tumor microenvironment (TME). A combination of bioinformatics and machine learning approaches was employed to perform statistical analyses.Additionally, flow cytometry was conducted to quantify T cell subtypes and assess biomarker expression in DCs. A BALB/c-derived xenograft mouse model was established to evaluate the functional role of MyD88 in tumor progression and immunotherapy response. Furthermore, immunohistochemical (IHC) staining was performed to reassess the biological effects of MyD88 in HCC patients undergoing immune checkpoint inhibitor (ICI) therapy.
Our pan-cancer data analysis further highlights the significant impact of MYD88 on clinical outcomes in HCC. Analysis of TCGA and GEO databases confirms that MYD88 serves as a key signaling molecule in DCs, reinforcing its critical role in immune regulation. Our experiments demonstrates that MyD88 modulates T cell function through DCs. , H22 tumor cells exhibited accelerated growth in MyD88 knockout mice and a reduced response to anti-PD-1 treatment, whereas wild-type mice showed the opposite trend.
These findings underscore the critical role of MYD88 in DC function, suggesting its potential as a biomarker for immunoregulation in HCC. By shaping the TME, MYD88 not only regulates the immune response in HCC but also influences patient clinical outcomes. Both ex vivo and experiments further validate that MYD88 impacts DC functionality, contributing to variations in HCC progression.
髓样分化初级反应蛋白88（MYD88）是一种关键的衔接蛋白，主要通过Toll样受体（TLR）和白细胞介素-1受体（IL-1R）信号传导介导免疫反应。TLR/MYD88通路在树突状细胞（DC）的成熟和功能中起关键作用，有助于机体的固有免疫。最近的研究进一步强调了MYD88在固有免疫中的关键作用及其对肝细胞癌（HCC）肿瘤微环境（TME）的调节影响。MYD88在DC中的表达及其在TME中的调节作用越来越受到关注。
从TCGA和GEO数据库检索的RNA测序数据用于我们特征的训练和验证。分析来自GEO的单细胞RNA转录组数据，以研究HCC肿瘤微环境（TME）中T细胞、髓样细胞和树突状细胞（DC）亚群之间的相关性。采用生物信息学和机器学习方法相结合进行统计分析。此外，进行流式细胞术以量化T细胞亚型并评估DC中的生物标志物表达。建立BALB/c来源的异种移植小鼠模型，以评估MyD88在肿瘤进展和免疫治疗反应中的功能作用。此外，进行免疫组织化学（IHC）染色以重新评估MyD88在接受免疫检查点抑制剂（ICI）治疗的HCC患者中的生物学效应。
我们的泛癌数据分析进一步突出了MYD88对HCC临床结局的重大影响。对TCGA和GEO数据库的分析证实，MYD88是DC中的关键信号分子，强化了其在免疫调节中的关键作用。我们的实验表明，MyD88通过DC调节T细胞功能。H22肿瘤细胞在MyD88基因敲除小鼠中生长加速，对抗PD-1治疗的反应降低，而野生型小鼠则呈现相反趋势。
这些发现强调了MYD88在DC功能中的关键作用，表明其作为HCC免疫调节生物标志物的潜力。通过塑造TME，MYD88不仅调节HCC中的免疫反应，还影响患者的临床结局。体外和体内实验进一步验证了MYD88影响DC功能，导致HCC进展的差异。
