美国耶鲁大学医学院严钦和Marcus W. Bosenberg团队合作取得一项新突破。他们发现KDM5B 通过招募 SETDB1 使逆转录元件沉默来促进免疫逃逸。相关论文发表在2021年10月20日出版的《自然》杂志上。

他们表明，在小鼠黑色素瘤模型中，KDM5B（一种对黑色素瘤维持和耐药性至关重要的 H3K4 去甲基化酶的消耗会诱导强烈的适应性免疫反应并增强对免疫检查点封锁的反应。从机制上讲，KDM5B 募集 H3K9 甲基转移酶 SETDB1 以不依赖去甲基化酶的方式抑制内源性逆转录元件，如MMVL30。这些逆转录因子的去抑制激活细胞质 RNA 感知和 DNA 感知途径以及随后的 I 型干扰素反应，导致肿瘤排斥和免疫记忆的诱导。他们的结果表明，KDM5B 通过逆转录元件的表观遗传沉默抑制抗肿瘤免疫。因此，他们揭示了 KDM5B 在黑色素瘤异染色质调节和免疫逃逸中的作用，为开发 KDM5B 靶向和 SETDB1 靶向疗法以增强肿瘤免疫原性和克服免疫疗法耐药性开辟了新途径。

据悉，肿瘤使用各种策略来逃避免疫监视。针对肿瘤免疫逃逸的免疫疗法，例如免疫检查点阻断，已对多种癌症显示出相当大的疗效，但由于原发性或获得性耐药，对大多数患者无效。最近的研究表明，一些表观遗传调节因子抑制抗肿瘤免疫，表明表观遗传疗法可以增强抗肿瘤免疫反应并克服对当前免疫疗法的抵抗。

附：英文原文

Title: KDM5B promotes immune evasion by recruiting SETDB1 to silence retroelements

Author: Zhang, Shang-Min, Cai, Wesley L., Liu, Xiaoni, Thakral, Durga, Luo, Jiesi, Chan, Lok Hei, McGeary, Meaghan K., Song, Eric, Blenman, Kim R. M., Micevic, Goran, Jessel, Shlomit, Zhang, Yangyi, Yin, Mingzhu, Booth, Carmen J., Jilaveanu, Lucia B., Damsky, William, Sznol, Mario, Kluger, Harriet M., Iwasaki, Akiko, Bosenberg, Marcus W., Yan, Qin

Issue&Volume: 2021-10-20

Abstract: Tumours use various strategies to evade immune surveillance1,2. Immunotherapies targeting tumour immune evasion such as immune checkpoint blockade have shown considerable efficacy on multiple cancers3,4 but are ineffective for most patients due to primary or acquired resistance5,6,7. Recent studies showed that some epigenetic regulators suppress anti-tumour immunity2,8,9,10,11,12, suggesting that epigenetic therapies could boost anti-tumour immune responses and overcome resistance to current immunotherapies. Here we show that, in mouse melanoma models, depletion of KDM5B—an H3K4 demethylase that is critical for melanoma maintenance and drug resistance13,14,15—induces robust adaptive immune responses and enhances responses to immune checkpoint blockade. Mechanistically, KDM5B recruits the H3K9 methyltransferase SETDB1 to repress endogenous retroelements such as MMVL30 in a demethylase-independent manner. Derepression of these retroelements activates cytosolic RNA-sensing and DNA-sensing pathways and the subsequent type-I interferon response, leading to tumour rejection and induction of immune memory. Our results demonstrate that KDM5B suppresses anti-tumour immunity by epigenetic silencing of retroelements. We therefore reveal roles of KDM5B in heterochromatin regulation and immune evasion in melanoma, opening new paths for the development of KDM5B-targeting and SETDB1-targeting therapies to enhance tumour immunogenicity and overcome immunotherapy resistance.

DOI: 10.1038/s41586-021-03994-2

Source: https://www.nature.com/articles/s41586-021-03994-2