Ablation of Histone Demethylase KDM5B in Melanoma Augments Anti-Tumor Immunity through Upregulation of Retroelements [RNA-Seq YUMMER1.7-Kdm5b KO]

Purpose: Advanced melanoma patients have poor prognosis. Although immune checkpoint blockade has revolutionized treatment for melanoma patients, majority of patients do not respond. The goal of this research is to evaluate whether epigenetic therapy targeting KDM5B could overcome resistance to immunotherapy. Methods:RNA-Seq analysis of KDM5B KO mouse melanoma cell lines compared to control cells to evaluate whether KDM5B depletion induces activation of retroelements, which subsequently activates type I interferon responses. Mouse studies were conducted to evaluate whether anti-tumor immunity induced by KDM5B loss could overcome immunotherapy resistance. Results: We identified that KDM5B depletion derepress retroelement expression, which subsequently activates type I interferon response and enhances anti-tumor immunity. Loss of KDM5B could overcome resistance to anti-PD-1 immunotherapy. Conclusions: Our work characterized ablation of histone demethylase KDM5B in melanoma augments anti-tumor immunity through Upregulation of retroelements. Overall design: RNA-seq analysis of KDM5B KO vs Control mouse melanoma cell lines; in vitro and in vivo functional study; molecular mechanism study

研究目的：晚期黑色素瘤患者预后不良。尽管免疫检查点阻断（immune checkpoint blockade）疗法已彻底革新了黑色素瘤的临床治疗方案，但多数患者仍无法对该疗法产生应答。本研究旨在评估靶向KDM5B的表观遗传治疗（epigenetic therapy）能否克服黑色素瘤对免疫治疗的耐药性。

研究方法：通过对KDM5B敲除（KDM5B KO）小鼠黑色素瘤细胞系与对照细胞开展RNA测序（RNA-Seq）分析，探究KDM5B缺失是否可诱导逆转录转座子（Retroelements）激活，进而激活I型干扰素应答；同时构建小鼠模型实验，评估KDM5B缺失诱导的抗肿瘤免疫能否克服免疫治疗耐药性。

研究结果：本研究证实，KDM5B缺失可解除逆转录转座子的表达抑制，进而激活I型干扰素应答并增强抗肿瘤免疫；KDM5B缺失能够有效克服抗PD-1免疫治疗的耐药性。

研究结论：本研究阐明，在黑色素瘤中敲除组蛋白去甲基化酶KDM5B（histone demethylase KDM5B），可通过上调逆转录转座子的表达水平增强抗肿瘤免疫。

实验整体设计：包含KDM5B敲除与对照小鼠黑色素瘤细胞系的RNA-seq分析、体外及体内功能实验，以及分子机制研究。