HIF1α epigenetically repressed macrophages via CRISPR/Cas9-EZH2 system for enhanced cancer immunotherapy.
HIF1α epigenetically repressed macrophages via CRISPR/Cas9-EZH2 system for enhanced cancer immunotherapy.
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HIF1α 通过 CRISPR/Cas9-EZH2 系统表观遗传抑制巨噬细胞以增强癌症免疫治疗
DOI：
10.1016/j.bioactmat.2021.02.008
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发表时间：
2021-09
影响因子：
18.9
通讯作者：
Liu L
中科院分区：
文献类型：
--
作者：
Dong Y;Zhang S;Gao X;Yin D;Wang T;Li Z;Wan Z;Wei M;Luo Y;Yang G;Liu L
肿瘤中的免疫抑制微环境已成为癌症免疫治疗的主要障碍。在本研究中，我们发现缺氧诱导因子1α（HIF1α）在肿瘤相关巨噬细胞中被激活，并成为免疫抑制微环境的一个重要因素。通过CRISPR/dCas9 - EZH2系统实现了启动子区域组蛋白H3甲基化对Hif1α的表观遗传沉默，其中组蛋白H3甲基转移酶EZH2被特异性地招募到启动子区域。Hif1α沉默的巨噬细胞，即HERM（Hif1α表观遗传抑制性巨噬细胞）表现出可遗传的肿瘤抑制表型。在皮下B16 - F10黑色素瘤同基因模型中，瘤内注射HERMs将免疫抑制微环境重编程为活跃状态，减轻了肿瘤负荷并延长了总体生存期。此外，HERMs治疗显著抑制了肿瘤血管生成。总之，我们的研究不仅确定了一个有希望的用于逆转免疫抑制微环境的细胞和分子靶点，还提供了一种通过表观遗传重编程的巨噬细胞对肿瘤微环境进行重编程的有效策略。
在缺氧微环境下，巨噬细胞被诱导通过抑制癌症免疫和促进血管生成来推动癌症进展。相反，经过改造的HERMs（Hif1α表观遗传抑制性巨噬细胞）对缺氧微环境有抗性，并通过解除免疫抑制和抑制肿瘤血管生成显著抑制肿瘤进展。
巨噬细胞在缺氧的肿瘤微环境下被诱导促进癌症进展。
HIF1α表观遗传抑制性巨噬细胞（HERM）具有抗肿瘤功能并抑制肿瘤进展。
HERMs解除免疫抑制并促进癌症免疫。
HERMs抑制肿瘤血管生成并减轻肿瘤负担。
Immune suppressive microenvironment in tumor emerges as the main obstacle for cancer immunotherapy. In this study, we identified that HIF1α was activated in the tumor associated macrophages and acted as an important factor for the immune suppressive microenvironment. Epigenetically silencing of Hif1α via histone H3 methylation in the promoter region was achieved by CRISPR/dCas9-EZH2 system, in which histone H3 methylase EZH2 was recruited to the promoter region specifically. The Hif1α silenced macrophage, namely HERM (Hif1α Epigenetically Repressed Macrophage) manifested as inheritable tumor suppressing phenotype. In the subcutaneous B16-F10 melanoma syngeneic model, intratumoral injection of HERMs reprogrammed the immune suppressive microenvironment to the active one, reducing tumor burden and prolonging overall survival. Additionally, HERMs therapy remarkably inhibited tumor angiogenesis. Together, our study has not only identified a promising cellular and molecular target for reverting immune suppressive microenvironment, but also provided a potent strategy for reprogramming tumor microenvironment via epigenetically reprogrammed macrophages. Under hypoxia microenvironment, macrophages are educated to promote cancer progression via inhibiting cancer immunity and enhancing angiogenesis. In contrast, the engineered HERMs (Hif1α Epigenetically Repressed Macrophages) are reluctant to the hypoxic microenvironment and significantly repress tumor progression via unleashing immune suppression and inhibiting tumor angiogenesis. Macrophage are trained to promote cancer progression under hypoxic tumor microenvironment. HIF1α epigenetically repressed macrophage (HERM) is characterized as anti-tumoral function and suppress tumor progression. HERMs unleash immune suppression and promote cancer immunity. HERMs inhibit tumor angiogenesis and reduce tumor burden.
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影响因子：
64.8
作者：
Guerriero JL;Sotayo A;Ponichtera HE;Castrillon JA;Pourzia AL;Schad S;Johnson SF;Carrasco RD;Lazo S;Bronson RT;Davis SP;Lobera M;Nolan MA;Letai A
通讯作者：
Letai A
影响因子：
8.8
作者：
Arwert EN;Harney AS;Entenberg D;Wang Y;Sahai E;Pollard JW;Condeelis JS
通讯作者：
Condeelis JS
影响因子：
21.3
作者：
Baer, Caroline;Squadrito, Mario Leonardo;De Palma, Michele
通讯作者：
De Palma, Michele
在癌症和其他炎症性疾病的情况下，巨噬细胞和中性粒细胞对缺氧的反应。
影响因子：
4.6
作者：
Egners A;Erdem M;Cramer T
通讯作者：
Cramer T
影响因子：
64.5
作者：
Chao MP;Alizadeh AA;Tang C;Myklebust JH;Varghese B;Gill S;Jan M;Cha AC;Chan CK;Tan BT;Park CY;Zhao F;Kohrt HE;Malumbres R;Briones J;Gascoyne RD;Lossos IS;Levy R;Weissman IL;Majeti R
通讯作者：
Majeti R