Background/Objectives: Melanoma remains a difficult malignancy to treat because it employs tolerance mechanisms like negative immune checkpoint (IC) molecules to avoid antitumor immune responses. Thus, immune checkpoint inhibitors (ICIs) are increasingly used to treat melanoma. However, many patients do not respond, indicating resistance mechanisms like intrinsic tumor characteristics and an immunosuppressive tumor microenvironment (TME). An inflamed TME was associated with improved ICI efficacy by upregulating the T-cell inflamed TME gene signatures, an array of genes associated with dendritic cells (DCs) and cytotoxic CD8+T-cell-mediated anti-tumor responses. As histone deacetylases (HDACs) have been shown to play crucial roles in regulating gene expression and aberrant HDAC expression has been reported in melanoma and also implicated in the regulation of IC, programmed cell death protein 1 (PD-1), and its ligand (PD-L1) and various immune evasion genes, we investigated the relationship between T-cell inflamed TME gene signatures and the HDAC family, particularly HDAC4.Methods: We used the skin cutaneous melanoma (SKCM) database, ICI-pretreated melanoma dataset, and other platforms including cBioPortal, TIMER 2.0, TISIDB, and UALCAN for the analysis.Results: We identified that high HDAC4 expression negatively modulated the TME by decreasing the abundance of DCs and cytotoxic CD8+T-cells. The group of melanoma patients with elevated HDAC4 expression exhibited not only poor prognosis but also diminished transcription of T-cell inflamed TME gene signatures and increased DNA methylation of T-cell inflamed TME gene signatures. Importantly, elevated HDAC4 expression was associated with decreased CD8+T-cells and a decreased ESTIMATE immune score in ICI-pretreated melanoma patients.Conclusions: Our findings suggest that HDAC4 may transform the TME into a non-inflamed phenotype, thereby reducing ICI efficacy in melanoma. Overall, this research shows that a combination of HDAC4 inhibitors and ICIs could result in better melanoma prognosis.
背景/目的：黑色素瘤因其利用负性免疫检查点（IC）分子等耐受机制来逃避抗肿瘤免疫应答，仍是一种难以治疗的恶性肿瘤。因此，免疫检查点抑制剂（ICIs）越来越多地用于治疗黑色素瘤。然而，许多患者对治疗无反应，这表明存在内在肿瘤特征和免疫抑制性肿瘤微环境（TME）等耐药机制。炎症性TME通过上调T细胞炎症性TME基因特征（一组与树突状细胞（DCs）和细胞毒性CD8+T细胞介导的抗肿瘤反应相关的基因）与改善ICI疗效相关。由于组蛋白去乙酰化酶（HDACs）已被证明在调节基因表达中起关键作用，且黑色素瘤中报道了异常的HDAC表达，并与IC、程序性细胞死亡蛋白1（PD-1）及其配体（PD-L1）以及各种免疫逃逸基因的调控有关，我们研究了T细胞炎症性TME基因特征与HDAC家族，特别是HDAC4之间的关系。 方法：我们使用皮肤黑色素瘤（SKCM）数据库、ICI预处理黑色素瘤数据集以及其他平台，包括cBioPortal、TIMER 2.0、TISIDB和UALCAN进行分析。 结果：我们发现高表达的HDAC4通过降低DCs和细胞毒性CD8+T细胞的丰度，对TME产生负向调节。HDAC4表达升高的黑色素瘤患者组不仅预后较差，而且T细胞炎症性TME基因特征的转录减少，其DNA甲基化增加。重要的是，在ICI预处理的黑色素瘤患者中，HDAC4表达升高与CD8+T细胞减少以及ESTIMATE免疫评分降低相关。 结论：我们的研究结果表明，HDAC4可能将TME转化为非炎症表型，从而降低ICI在黑色素瘤中的疗效。总体而言，这项研究表明，HDAC4抑制剂与ICIs联合使用可能会改善黑色素瘤的预后。
肿瘤(癌症)患者之家