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缺氧诱导因子1α（HIF1α）通过CRISPR/Cas9 - EZH2系统对巨噬细胞进行表观遗传抑制，以增强癌症免疫治疗效果。

HIF1α epigenetically repressed macrophages via CRISPR/Cas9-EZH2 system for enhanced cancer immunotherapy.

作者信息

Dong Yan, Zhang Siyan, Gao Xiaotong, Yin Dandan, Wang Tingting, Li Zhelong, Wan Zhuo, Wei Mengying, Luo Ying, Yang Guodong, Liu Li

机构信息

Department of Hematology, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, People's Republic of China.

Department of Ultrasound Diagnostics, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, People's Republic of China.

出版信息

Bioact Mater. 2021 Feb 20;6(9):2870-2880. doi: 10.1016/j.bioactmat.2021.02.008. eCollection 2021 Sep.

DOI:10.1016/j.bioactmat.2021.02.008
PMID:33718668
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7905236/
Abstract

Immune suppressive microenvironment in tumor emerges as the main obstacle for cancer immunotherapy. In this study, we identified that HIF1 was activated in the tumor associated macrophages and acted as an important factor for the immune suppressive microenvironment. Epigenetically silencing of 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 silenced macrophage, namely HERM ( 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.

摘要

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1（HIF1）在肿瘤相关巨噬细胞中被激活，并作为免疫抑制微环境的一个重要因素发挥作用。通过CRISPR/dCas9-EZH2系统实现了通过组蛋白H3在启动子区域甲基化对其进行表观遗传沉默，其中组蛋白H3甲基转移酶EZH2被特异性招募到启动子区域。这种沉默的巨噬细胞，即HERM（表观遗传抑制巨噬细胞）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HERM可将免疫抑制微环境重编程为活性微环境，减轻肿瘤负担并延长总生存期。此外，HERM疗法显著抑制肿瘤血管生成。总之，我们的研究不仅确定了一个用于逆转免疫抑制微环境的有前景的细胞和分子靶点，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。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9cc/7905236/2f92866ffa3d/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9cc/7905236/9dd4cd401c6e/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9cc/7905236/7cb9b5bb2eef/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9cc/7905236/531ba85b6efe/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9cc/7905236/70e6e2d1bb6f/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9cc/7905236/ed9f19bd9362/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9cc/7905236/204f19fba2bd/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9cc/7905236/179598d7667c/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9cc/7905236/2f92866ffa3d/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9cc/7905236/9dd4cd401c6e/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9cc/7905236/7cb9b5bb2eef/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9cc/7905236/531ba85b6efe/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9cc/7905236/70e6e2d1bb6f/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9cc/7905236/ed9f19bd9362/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9cc/7905236/204f19fba2bd/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9cc/7905236/179598d7667c/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9cc/7905236/2f92866ffa3d/gr7.jpg

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