Enhancer decommissioning by MLL4 ablation elicits dsRNA-interferon signaling and GSDMD-mediated pyroptosis to potentiate anti-tumor immunity.
Enhancer decommissioning by MLL4 ablation elicits dsRNA-interferon signaling and GSDMD-mediated pyroptosis to potentiate anti-tumor immunity.
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MLL4 消融引起的增强子停用引发 dsRNA 干扰素信号传导和 GSDMD 介导的细胞焦亡，从而增强抗肿瘤免疫
DOI：
10.1038/s41467-022-34253-1
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发表时间：
2022-11-02
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
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作者：
增强子去调控是一种成熟的促肿瘤机制，但它是否在肿瘤免疫中起到调节作用在很大程度上还不清楚。在这里，我们证明了混合系白血病3和4(ML3和MLL4，分别也被称为KMT2C和KMT2D)，两个增强子相关的组蛋白H3赖氨酸4(H3K4)单甲基转移酶的肿瘤细胞切除，增加了肿瘤的免疫原性，促进了抗肿瘤T细胞应答。机制上，MLL4通过去激活增强子/超增强子抑制RNA诱导的沉默复合体(RISC)和DNA甲基转移酶的表达，从而分别导致双链RNA(DsRNA)干扰素反应和Gasdermin D(GSDMD)介导的热下垂的转录重新激活。更重要的是，我们揭示了dsRNA-干扰素信号和GSDMD介导的上睑下垂对于增强抗肿瘤免疫和改善MLL4消融肿瘤的免疫治疗效果都是至关重要的。因此，我们的发现建立了肿瘤细胞增强剂作为免疫逃避机制的额外一层，并提示靶向增强剂或其上游和/或下游分子通路来克服癌症患者的免疫治疗耐药性的潜力。增强子去调节在抗肿瘤免疫中的作用仍有待探讨。在这里，作者认为，切除两种增强子相关的H3K4单甲基转移酶ML3和MLL4，可以提高肿瘤的免疫原性，促进抗肿瘤T细胞应答。
Enhancer deregulation is a well-established pro-tumorigenic mechanism but whether it plays a regulatory role in tumor immunity is largely unknown. Here, we demonstrate that tumor cell ablation of mixed-lineage leukemia 3 and 4 (MLL3 and MLL4, also known as KMT2C and KMT2D, respectively), two enhancer-associated histone H3 lysine 4 (H3K4) mono-methyltransferases, increases tumor immunogenicity and promotes anti-tumor T cell response. Mechanistically, MLL4 ablation attenuates the expression of RNA-induced silencing complex (RISC) and DNA methyltransferases through decommissioning enhancers/super-enhancers, which consequently lead to transcriptional reactivation of the double-stranded RNA (dsRNA)-interferon response and gasdermin D (GSDMD)-mediated pyroptosis, respectively. More importantly, we reveal that both the dsRNA-interferon signaling and GSDMD-mediated pyroptosis are of critical importance to the increased anti-tumor immunity and improved immunotherapeutic efficacy in MLL4-ablated tumors. Thus, our findings establish tumor cell enhancers as an additional layer of immune evasion mechanisms and suggest the potential of targeting enhancers or their upstream and/or downstream molecular pathways to overcome immunotherapeutic resistance in cancer patients. The role of enhancer de-regulation in anti-tumor immunity remains to be explored. Here, the authors suggest that ablation of MLL3 and MLL4, two enhancer-associated H3K4 monomethyltransferases, increases tumor immunogenicity and promotes anti-tumor T cell response.
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DOI：
10.1126/science.aac9935
发表时间：
2016-04-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Casey SC;Tong L;Li Y;Do R;Walz S;Fitzgerald KN;Gouw AM;Baylot V;Gütgemann I;Eilers M;Felsher DW
通讯作者：
Felsher DW
影响因子：
12.3
作者：
Jansz N;Faulkner GJ
通讯作者：
Faulkner GJ
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
50.3
作者：
Gide, Tuba N.;Quek, Camelia;Wilmott, James S.
通讯作者：
Wilmott, James S.
影响因子：
64.5
作者：
Hugo W;Zaretsky JM;Sun L;Song C;Moreno BH;Hu-Lieskovan S;Berent-Maoz B;Pang J;Chmielowski B;Cherry G;Seja E;Lomeli S;Kong X;Kelley MC;Sosman JA;Johnson DB;Ribas A;Lo RS
通讯作者：
Lo RS