HIF1α Epigenetically Repressed Macrophages Via CRISPR/Cas9-EZH2 System for Enhanced Cancer Immunotherapy

Overview

Journal Bioact Mater

Specialty Biomedical Engineering

Date 2021 Mar 15

PMID 33718668

Citations 11

Authors

Yan Dong

Siyan Zhang

Xiaotong Gao

Dandan Yin

Tingting Wang

Zhelong Li

Zhuo Wan

Mengying Wei

Ying Luo

Guodong Yang

Li Liu

Affiliations

Soon will be listed here.

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.

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References

Gordon S, Maute R, Dulken B, Hutter G, George B, McCracken M . PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature. 2017; 545(7655):495-499. PMC: 5931375. DOI: 10.1038/nature22396. View

Pannell M, Labuz D, Celik M, Keye J, Batra A, Siegmund B . Adoptive transfer of M2 macrophages reduces neuropathic pain via opioid peptides. J Neuroinflammation. 2016; 13(1):262. PMC: 5055715. DOI: 10.1186/s12974-016-0735-z. View

Hou X, Zhang X, Zhao W, Zeng C, Deng B, McComb D . Vitamin lipid nanoparticles enable adoptive macrophage transfer for the treatment of multidrug-resistant bacterial sepsis. Nat Nanotechnol. 2020; 15(1):41-46. PMC: 7181370. DOI: 10.1038/s41565-019-0600-1. View

Chao M, Alizadeh A, Tang C, Myklebust J, Varghese B, Gill S . Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma. Cell. 2010; 142(5):699-713. PMC: 2943345. DOI: 10.1016/j.cell.2010.07.044. View

Gu L, Mooney D . Biomaterials and emerging anticancer therapeutics: engineering the microenvironment. Nat Rev Cancer. 2015; 16(1):56-66. PMC: 4790726. DOI: 10.1038/nrc.2015.3. View

Adams S, Kozhaya L, Martiniuk F, Meng T, Chiriboga L, Liebes L . Topical TLR7 agonist imiquimod can induce immune-mediated rejection of skin metastases in patients with breast cancer. Clin Cancer Res. 2012; 18(24):6748-57. PMC: 3580198. DOI: 10.1158/1078-0432.CCR-12-1149. View

Corzo C, Condamine T, Lu L, Cotter M, Youn J, Cheng P . HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J Exp Med. 2010; 207(11):2439-53. PMC: 2964584. DOI: 10.1084/jem.20100587. View

Tariq M, Zhang J, Liang G, Ding L, He Q, Yang B . Macrophage Polarization: Anti-Cancer Strategies to Target Tumor-Associated Macrophage in Breast Cancer. J Cell Biochem. 2017; 118(9):2484-2501. DOI: 10.1002/jcb.25895. View

Wang X, Luo G, Zhang K, Cao J, Huang C, Jiang T . Hypoxic Tumor-Derived Exosomal miR-301a Mediates M2 Macrophage Polarization via PTEN/PI3Kγ to Promote Pancreatic Cancer Metastasis. Cancer Res. 2018; 78(16):4586-4598. DOI: 10.1158/0008-5472.CAN-17-3841. View

10.

Vitale I, Manic G, Coussens L, Kroemer G, Galluzzi L . Macrophages and Metabolism in the Tumor Microenvironment. Cell Metab. 2019; 30(1):36-50. DOI: 10.1016/j.cmet.2019.06.001. View

11.

Willingham S, Volkmer J, Gentles A, Sahoo D, Dalerba P, Mitra S . The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci U S A. 2012; 109(17):6662-7. PMC: 3340046. DOI: 10.1073/pnas.1121623109. View

12.

Marra M, Salzano G, Leonetti C, Tassone P, Scarsella M, Zappavigna S . Nanotechnologies to use bisphosphonates as potent anticancer agents: the effects of zoledronic acid encapsulated into liposomes. Nanomedicine. 2011; 7(6):955-64. DOI: 10.1016/j.nano.2011.03.004. View

13.

Andreesen R, Scheibenbogen C, Brugger W, Krause S, Meerpohl H, Leser H . Adoptive transfer of tumor cytotoxic macrophages generated in vitro from circulating blood monocytes: a new approach to cancer immunotherapy. Cancer Res. 1990; 50(23):7450-6. View

14.

Weiskopf K, Ring A, Ho C, Volkmer J, Levin A, Volkmer A . Engineered SIRPα variants as immunotherapeutic adjuvants to anticancer antibodies. Science. 2013; 341(6141):88-91. PMC: 3810306. DOI: 10.1126/science.1238856. View

15.

Henze A, Mazzone M . The impact of hypoxia on tumor-associated macrophages. J Clin Invest. 2016; 126(10):3672-3679. PMC: 5096805. DOI: 10.1172/JCI84427. View

16.

Egners A, Erdem M, Cramer T . The Response of Macrophages and Neutrophils to Hypoxia in the Context of Cancer and Other Inflammatory Diseases. Mediators Inflamm. 2016; 2016:2053646. PMC: 4789443. DOI: 10.1155/2016/2053646. View

17.

Konermann S, Brigham M, Trevino A, Joung J, Abudayyeh O, Barcena C . Genome-scale transcriptional activation by an engineered CRISPR-Cas9 complex. Nature. 2014; 517(7536):583-8. PMC: 4420636. DOI: 10.1038/nature14136. View

18.

Arwert E, Harney A, Entenberg D, Wang Y, Sahai E, Pollard J . A Unidirectional Transition from Migratory to Perivascular Macrophage Is Required for Tumor Cell Intravasation. Cell Rep. 2018; 23(5):1239-1248. PMC: 5946803. DOI: 10.1016/j.celrep.2018.04.007. View

19.

Rankin E, Giaccia A . Hypoxic control of metastasis. Science. 2016; 352(6282):175-80. PMC: 4898055. DOI: 10.1126/science.aaf4405. View

20.

Imtiyaz H, Williams E, Hickey M, Patel S, Durham A, Yuan L . Hypoxia-inducible factor 2alpha regulates macrophage function in mouse models of acute and tumor inflammation. J Clin Invest. 2010; 120(8):2699-714. PMC: 2912179. DOI: 10.1172/JCI39506. View