PRC2-Mediated Epigenetic Suppression of Type I IFN-STAT2 Signaling Impairs Antitumor Immunity in Luminal Breast Cancer.
PRC2-Mediated Epigenetic Suppression of Type I IFN-STAT2 Signaling Impairs Antitumor Immunity in Luminal Breast Cancer.
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DOI：
10.1158/0008-5472.can-22-0736
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发表时间：
2022-12-16
期刊：
影响因子：
11.2
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中科院分区：
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某些癌症类型中的免疫抑制肿瘤微环境，如管腔乳腺癌，支持肿瘤生长并限制治疗效果。确定诱导免疫刺激环境的方法可能有助于改善癌症治疗。在这里，我们证明了抑制癌症固有的EZH2促进了雌激素受体α阳性(ERα+)乳腺癌的抗肿瘤免疫。EZH2是PRC2复合体的一个组成部分，它催化组蛋白H3在赖氨酸27(H3K27me3)上的三甲基化。53个基因的PrC2活性特征与ERα+乳腺癌细胞的免疫反应密切相关。抑制EZH2对免疫监视的刺激作用需要I型干扰素信号的特异性激活。对PRC2抑制基因和全基因组H3K27me3图谱的综合分析表明，H3K27me3使I型干扰素配体表观遗传沉默。值得注意的是，转录因子STAT2而不是STAT1介导了I型干扰素信号的免疫刺激功能。在EZH2被抑制后，即使在没有细胞因子的情况下，STAT2也被招募到干扰素刺激基因的启动子，这表明形成了一个自分泌的干扰素-STAT2轴。在腔性乳腺癌患者中，高水平的EZH2和低水平的STAT2与最差的抗肿瘤免疫反应有关。总而言之，这项工作为开发一种有效的治疗策略铺平了道路，该策略可能会逆转癌症的免疫抑制。
The immunosuppressive tumor microenvironment in some cancer types, such as luminal breast cancer, supports tumor growth and limits therapeutic efficacy. Identifying approaches to induce an immunostimulatory environment could help improve cancer treatment. Here, we demonstrate that inhibition of cancer-intrinsic EZH2 promotes antitumor immunity in estrogen receptor α-positive (ERα+) breast cancer. EZH2 is a component of the PRC2 complex, which catalyzes trimethylation of histone H3 at lysine 27 (H3K27me3). A 53-gene PRC2 activity signature was closely associated with the immune responses of ERα+ breast cancer cells. The stimulatory effects of EZH2 inhibition on immune surveillance required specific activation of type I interferon (IFN) signaling. Integrative analysis of PRC2-repressed genes and genome-wide H3K27me3 landscape revealed that type I IFN ligands are epigenetically silenced by H3K27me3. Notably, the transcription factor STAT2, but not STAT1, mediated the immunostimulatory functions of type I IFN signaling. Following EZH2 inhibition, STAT2 was recruited to the promoters of IFN-stimulated genes even in the absence of the cytokines, suggesting the formation of an autocrine IFN-STAT2 axis. In patients with luminal breast cancer, high levels of EZH2 and low levels of STAT2 were associated with the worst antitumor immune responses. Collectively, this work paves the way for the development of an effective therapeutic strategy that may reverse immunosuppression in cancer.