Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA.
Department of Urology, Columbia University Irving Medical Center, New York, NY 10032, USA.
Mol Cell. 2022 Oct 20;82(20):3901-3918.e7. doi: 10.1016/j.molcel.2022.09.007. Epub 2022 Oct 6.
How cancer-associated chromatin abnormalities shape tumor-immune interaction remains incompletely understood. Recent studies have linked DNA hypomethylation and de-repression of retrotransposons to anti-tumor immunity through the induction of interferon response. Here, we report that inactivation of the histone H3K36 methyltransferase NSD1, which is frequently found in squamous cell carcinomas (SCCs) and induces DNA hypomethylation, unexpectedly results in diminished tumor immune infiltration. In syngeneic and genetically engineered mouse models of head and neck SCCs, NSD1-deficient tumors exhibit immune exclusion and reduced interferon response despite high retrotransposon expression. Mechanistically, NSD1 loss results in silencing of innate immunity genes, including the type III interferon receptor IFNLR1, through depletion of H3K36 di-methylation (H3K36me2) and gain of H3K27 tri-methylation (H3K27me3). Inhibition of EZH2 restores immune infiltration and impairs the growth of Nsd1-mutant tumors. Thus, our work uncovers a druggable chromatin cross talk that regulates the viral mimicry response and enables immune evasion of DNA hypomethylated tumors.
癌症相关染色质异常如何影响肿瘤与免疫的相互作用尚不完全清楚。最近的研究表明，DNA 低甲基化和逆转座子的去抑制与干扰素反应的诱导有关，从而促进抗肿瘤免疫。在这里，我们报告组蛋白 H3K36 甲基转移酶 NSD1 的失活，它在鳞状细胞癌（SCC）中经常发现，并诱导 DNA 低甲基化，出乎意料地导致肿瘤免疫浸润减少。在头颈 SCC 的同源和基因工程小鼠模型中，尽管逆转座子表达水平高，但 NSD1 缺陷型肿瘤表现出免疫排斥和干扰素反应减少。从机制上讲，NSD1 的缺失导致先天免疫基因沉默，包括 III 型干扰素受体 IFNLR1，这是通过耗尽 H3K36 二甲基化（H3K36me2）和获得 H3K27 三甲基化（H3K27me3）实现的。EZH2 的抑制恢复了免疫浸润，并损害了 Nsd1 突变型肿瘤的生长。因此，我们的工作揭示了一种可药物化的染色质串扰，它调节病毒模拟反应，并使 DNA 低甲基化肿瘤能够逃避免疫。
