Targeting Deltex E3 Ubiquitin Ligase 2 Inhibits Tumor‐associated Neutrophils and Sensitizes Hepatocellular Carcinoma Cells to Immunotherapy
Several E3 ligases have been found to affect the immune microenvironment of hepatocellular carcinoma (HCC) and lead to the resistance of immunotherapy. In this study, genes of E3 ligases are screened based on The Cancer Genome Atlas (TCGA) dataset. Through cytometry by time of flight (CyTOF), flow cytometry, and further experiments, Deltex E3 ubiquitin ligase 2 (DTX2) in HCC cells is identified to promote the infiltration and polarization of tumor-associated neutrophils (TANs) with a protumor phenotype, thus attenuating the infiltration and cytotoxicity of CD8+ T cells partially through C-X-C motif chemokine 2 (CXCL2) and C-X-C motif chemokine 6 (CXCL6). Mechanistically, DTX2 can interact with histone H2B and promote its monoubiquitination at lysine120 (H2BK120ub1), thereby increasing CXCL2 and CXCL6 transcription through histone epigenetic regulation. Different tumor models in vivo demonstrated that DTX2 inhibitor treatment inhibited tumor growth and sensitized HCC cells to the therapeutic effects of programmed cell death protein 1 (PD-1) antibody. In summary, this study identifies DTX2 as a potential target for HCC immunotherapy.
Authors
- Jiafeng Chen (ORCID: https://orcid.org/0000-0002-1088-5338)
- Wei‐Feng Qu
- Tianhao Chu (ORCID: https://orcid.org/0000-0001-9910-9361)
- Jian Zhou (ORCID: https://orcid.org/0000-0002-8654-6439)
- Fangyu Chen (ORCID: https://orcid.org/0000-0002-4512-7190)
- Rui Yang (ORCID: https://orcid.org/0000-0001-9126-4957)
- Zheng Tang (ORCID: https://orcid.org/0000-0002-8604-5386)
- Gui‐Qi Zhu (ORCID: https://orcid.org/0000-0001-5089-6923)
- Zhong Zhen Guan (ORCID: https://orcid.org/0000-0003-4808-7400)
- Shanhua Mao (ORCID: https://orcid.org/0000-0002-8647-4148)
- Ying‐Hong Shi (ORCID: https://orcid.org/0000-0002-1833-8988)
- Yi Wang (ORCID: https://orcid.org/0000-0002-9974-7440)
- Jia Fan
- Yuanyuan Ruan (ORCID: https://orcid.org/0000-0003-2877-8642)
- Xiaoling Wu (ORCID: https://orcid.org/0000-0002-2534-8375)
- Yiran Chen (ORCID: https://orcid.org/0000-0002-9507-4007)
- Yuan Fang (ORCID: https://orcid.org/0000-0002-1931-2632)
- Jun Gao
- Shushu Song (ORCID: https://orcid.org/0000-0001-6261-8664)
- Qianfu Zhao
- Yichao Bu (ORCID: https://orcid.org/0009-0002-1283-3547)
- Weiren Liu
Institutions
- Ministry of Education of the People's Republic of China (CN)
- Sun Yat-sen University (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Fudan University (CN)
- Shanghai Institute of Organic Chemistry (CN)
- Zhongshan Hospital (CN)
- The First Affiliated Hospital, Sun Yat-sen University (CN)
Publication Details
- Journal
- Advanced Science
- Published
- 2024-12-29
- DOI
- https://doi.org/10.1002/advs.202408233
- Citations
- 8
- Primary Topic
- Immune cells in cancer
- Type
- article
- Field-Weighted Citation Impact
- 1.92
Funders
- Shanghai Municipal Health Commission
- National Natural Science Foundation of China
- National Key Research and Development Program of China