Nano‐Regulator Inhibits Tumor Immune Escape via the “Two‐Way Regulation” Epigenetic Therapy Strategy

Author:

Liang Shuang1,Liu Meichen1,Mu Weiwei1,Gao Tong1,Gao Shuying1,Fu Shunli1,Yuan Shijun1,Liu Jinhu1,Liu Yongjun1,Jiang Dandan2,Zhang Na1ORCID

Affiliation:

1. Department of Pharmaceutics Key Laboratory of Chemical Biology (Ministry of Education) School of Pharmaceutical Sciences Cheeloo College of Medicine Shandong University 44 Wenhua Xi Road Jinan Shandong 250012 China

2. Department of Pharmacy Henan Provincial People's Hospital People's Hospital of Zhengzhou University Zhengzhou Henan 450003 China

Abstract

AbstractTumor immune escape caused by low levels of tumor immunogenicity and immune checkpoint‐dependent suppression limits the immunotherapeutic effect. Herein, a “two‐way regulation” epigenetic therapeutic strategy is proposed using a novel nano‐regulator that inhibits tumor immune escape by upregulating expression of tumor‐associated antigens (TAAs) to improve immunogenicity and downregulating programmed cell death 1 ligand 1 (PD‐L1) expression to block programmed death‐1 (PD‐1)/PD‐L1. To engineer the nano‐regulator, the DNA methyltransferase (DNMT) inhibitor zebularine (Zeb) and the bromodomain‐containing protein 4 (BRD4) inhibitor JQ1 are co‐loaded into the cationic liposomes with condensing the toll‐like receptor 9 (TLR9) agonist cytosine‐phosphate‐guanine (CpG) via electrostatic interactions to obtain G‐J/ZL. Then, asparagine–glycine–arginine (NGR) modified material carboxymethyl‐chitosan (CMCS) is coated on the surface of G‐J/ZL to construct CG‐J/ZL. CG‐J/ZL is shown to target tumor tissue and disassemble under the acidic tumor microenvironment (TME). Zeb upregulated TAAs expression to improve the immunogenicity; JQ1 inhibited PD‐L1 expression to block immune checkpoint; CpG promote dendritic cell (DC) maturation and reactivated the ability of tumour‐associated macrophages (TAM) to kill tumor cells. Taken together, these results demonstrate that the nano‐regulator CG‐J/ZL can upregulate TAAs expression to enhance T‐cell infiltration and downregulate PD‐L1 expression to improve the recognition of tumor cells by T‐cells, representing a promising strategy to improve antitumor immune response.

Funder

National Natural Science Foundation of China

Publisher

Wiley

Subject

General Physics and Astronomy,General Engineering,Biochemistry, Genetics and Molecular Biology (miscellaneous),General Materials Science,General Chemical Engineering,Medicine (miscellaneous)

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