小柯机器人

美国哈佛医学院Bradley E. Bernstein、Robert T. Manguso等研究人员合作发现，SETDB1的表观遗传沉默抑制肿瘤固有的免疫原性。这一研究成果于2021年5月5日在线发表在国际学术期刊《自然》上。

为了确定调节癌细胞免疫敏感性的因素，研究人员在经过免疫检查点阻断治疗的小鼠肿瘤模型中进行了针对936染色质调节因子的体内CRISPR–Cas9筛选。研究人员发现，H3K9甲基转移酶SETDB1和HUSH和KAP1复合体的其他成员是免疫逃逸的介导因子。研究人员还发现，人类肿瘤中SETDB1（1q21.3）的扩增与免疫排斥和对免疫检查点阻断的耐药有关。SETDB1抑制大量域，主要是在开放的基因组区室中。

这些域富含转座因子（TEs）和与片段复制事件相关的免疫簇，而片段复制事件是基因组进化的核心机制。SETDB1丢失可抑制这些区域中潜在的TE衍生调控元件、免疫刺激基因和TE编码的逆转录病毒抗原，并在体内触发TE特异性细胞毒性T细胞应答。这项研究表明，SETDB1可作为抑制肿瘤固有免疫原性的表观遗传检查点，因此是免疫治疗的候选靶点。

据悉，表观遗传失调是肿瘤发生的决定性特征，与免疫逃逸有关。

附：英文原文

Title: Epigenetic silencing by SETDB1 suppresses tumour intrinsic immunogenicity

Author: Gabriel K. Griffin, Jingyi Wu, Arvin Iracheta-Vellve, James C. Patti, Jeffrey Hsu, Thomas Davis, Deborah Dele-Oni, Peter P. Du, Aya G. Halawi, Jeffrey J. Ishizuka, Sarah Y. Kim, Susan Klaeger, Nelson H. Knudsen, Brian C. Miller, Tung H. Nguyen, Kira E. Olander, Malvina Papanastasiou, Suzanna Rachimi, Emily J. Robitschek, Emily M. Schneider, Mitchell D. Yeary, Margaret D. Zimmer, Jacob D. Jaffe, Steven A. Carr, John G. Doench, W. Nicholas Haining, Kathleen B. Yates, Robert T. Manguso, Bradley E. Bernstein

Issue&Volume: 2021-05-05

Abstract: Epigenetic dysregulation is a defining feature of tumorigenesis that is implicated in immune escape1,2. Here, to identify factors that modulate the immune sensitivity of cancer cells, we performed in vivo CRISPR–Cas9 screens targeting 936 chromatin regulators in mouse tumour models treated with immune checkpoint blockade. We identified the H3K9 methyltransferase SETDB1 and other members of the HUSH and KAP1 complexes as mediators of immune escape3,4,5. We also found that amplification of SETDB1 (1q21.3) in human tumours is associated with immune exclusion and resistance to immune checkpoint blockade. SETDB1 represses broad domains, primarily within the open genome compartment. These domains are enriched for transposable elements (TEs) and immune clusters associated with segmental duplication events, a central mechanism of genome evolution6. SETDB1 loss derepresses latent TE-derived regulatory elements, immunostimulatory genes, and TE-encoded retroviral antigens in these regions, and triggers TE-specific cytotoxic T cell responses in vivo. Our study establishes SETDB1 as an epigenetic checkpoint that suppresses tumour-intrinsic immunogenicity, and thus represents a candidate target for immunotherapy.

DOI: 10.1038/s41586-021-03520-4

Source: https://www.nature.com/articles/s41586-021-03520-4

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html