J Cancer 2022; 13(7):2126-2137. doi:10.7150/jca.69375 This issue

Research Paper

BET inhibitor JQ1 enhances anti-tumor immunity and synergizes with PD-1 blockade in CRC

Huijin Wang1,2#, Guangyao Liu1,2#, Xinghan Jin1,2, Shenglei Song1,2, Songyao Chen1,2, Peiqing Zhou1, Huan Li1,2, Jianming Liang1,2, Bo Li1✉, Changhua Zhang1,2✉, Yulong He1,2✉

1. Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, No.628, Zhenyuan Road, Guangming District, Shenzhen, 518107, China
2. Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan 2nd Road, Guangzhou, Guangdong, 510080, China
# These authors contributed equally to this work.

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Citation:
Wang H, Liu G, Jin X, Song S, Chen S, Zhou P, Li H, Liang J, Li B, Zhang C, He Y. BET inhibitor JQ1 enhances anti-tumor immunity and synergizes with PD-1 blockade in CRC. J Cancer 2022; 13(7):2126-2137. doi:10.7150/jca.69375. Available from https://www.jcancer.org/v13p2126.htm

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Abstract

Graphic abstract

Most colorectal cancer (CRC) patients are insensitive to immune checkpoint inhibitors (ICIs) due to the immunosuppressive tumor microenvironment (TME). Epigenetic factors such as the bromo-and extraterminal domain (BET) family proteins may be responsible for the immunosuppressive microenvironment. Previous studies have shown that inhibitors of BET family proteins have the potential to remodel the immunosuppressive TME. However, data on the role of BET inhibitors in immune microenvironment in CRC remains unclear. Here, we evaluated the immunoregulatory role of JQ1, a BET inhibitor, in CRC. Transcriptome sequencing data showed that JQ1 decreased CD274 expression and increased H2Kb expression in MC38 cells. Flow cytometry assays demonstrated that JQ1 decreased cell-surface PD-L1 expression in MC38 and HCT116 cells. Moreover, JQ1 significantly increased cell-surface expression of major histocompatibility complex class I (MHC-I) in MC38 cells and HCT116 cells. Antigen-specific cytotoxic T lymphocytes (CTLs) assay demonstrated that JQ1 enhanced the MHC-I-mediated cytotoxicity of CTLs. Mouse colon cancer cell line MC38 was used to establish the syngeneic mouse tumor model. Compared with the control, JQ1 significantly inhibited tumor growth and prolonged the overall survival of the mice. Besides, JQ1 did not only inhibit tumor growth by enhancing anti-tumor immunity, but also promoted the anti-tumor effect of PD-1 antibody. In addition, our data showed that JQ1 reduced infiltration of intratumoral regulatory T cells (Treg), thus remodeling the immunosuppressive TME. Taken together, these results highlight a new approach that enhances anti-PD-1 sensitivity in CRC.

Keywords: Colorectal cancer, JQ1, immunotherapy, immunosuppression.