Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
Department of Microbiology, Immunology and Molecular Genetics, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
Cancer Res. 2022 Dec 16;82(24):4624-4640. doi: 10.1158/0008-5472.CAN-22-0736.
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 polycomb-repressive complex 2 (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 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.
Inhibition of EZH2 activates a type I IFN-STAT2 signaling axis and provides a therapeutic strategy to stimulate antitumor immunity and therapy responsiveness in immunologically cold luminal breast cancer.
在某些癌症类型中，如腔乳腺癌，免疫抑制性肿瘤微环境支持肿瘤生长并限制治疗效果。鉴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，我们证明抑制癌症内在 EZH2 可促进雌激素受体 α 阳性（ERα+）乳腺癌中的抗肿瘤免疫。EZH2 是多梳抑制复合物 2（PRC2）复合物的组成部分，该复合物催化组蛋白 H3 赖氨酸 27（H3K27me3）的三甲基化。PRC2 活性的 53 个基因特征与 ERα+乳腺癌细胞的免疫反应密切相关。EZH2 抑制对免疫监视的刺激作用需要 I 型 IFN 信号的特异性激活。PRC2 抑制基因和全基因组 H3K27me3 景观的综合分析表明，I 型 IFN 配体通过 H3K27me3 被表观遗传沉默。值得注意的是，转录因子 STAT2 而不是 STAT1 介导了 I 型 IFN 信号的免疫刺激功能。在 EZH2 抑制后，STAT2 被募集到 IFN 刺激基因的启动子上，即使没有细胞因子，这表明形成了自分泌 IFN-STAT2 轴。在腔乳腺癌患者中，EZH2 水平高和 STAT2 水平低与抗肿瘤免疫反应最差相关。总的来说，这项工作为开发有效的治疗策略铺平了道路，该策略可能逆转癌症中的免疫抑制。
抑制 EZH2 激活了 I 型 IFN-STAT2 信号轴，并提供了一种治疗策略，可刺激免疫冷的腔乳腺癌中的抗肿瘤免疫和治疗反应性。
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