Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Nature. 2021 Jul;595(7866):309-314. doi: 10.1038/s41586-021-03520-4. Epub 2021 May 5.
Epigenetic dysregulation is a defining feature of tumorigenesis that is implicated in immune escape. 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 escape. 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 evolution. 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.
表观遗传失调是肿瘤发生的一个特征，它与免疫逃逸有关。在这里，为了确定调节癌细胞免疫敏感性的因素，我们在接受免疫检查点阻断治疗的小鼠肿瘤模型中，针对 936 种染色质调节剂进行了体内 CRISPR-Cas9 筛选。我们发现 H3K9 甲基转移酶 SETDB1 和 HUSH 和 KAP1 复合物的其他成员是免疫逃逸的介质。我们还发现，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性有关。SETDB1 抑制广泛的结构域，主要在开放基因组区室中。这些结构域富含转座元件 (TEs) 和与片段重复事件相关的免疫簇，这是基因组进化的一个核心机制。SETDB1 的缺失使潜伏的 TE 衍生调节元件、免疫刺激基因和这些区域中 TE 编码的逆转录病毒抗原去抑制，并在体内引发 TE 特异性细胞毒性 T 细胞反应。我们的研究确立了 SETDB1 作为一种表观遗传检查点，抑制肿瘤内在的免疫原性，因此代表了免疫治疗的一个候选靶点。
