Targeting Deltex E3 Ubiquitin Ligase 2 Inhibits Tumor-associated Neutrophils and Sensitizes Hepatocellular Carcinoma Cells to Immunotherapy

Xiaoling Wu; Jiafeng Chen; Yiran Chen; Shushu Song; Yuan Fang; Shengwei Mao; Jun Gao; Guiqi Zhu; Weifeng Qu; Qianfu Zhao; Rui Yang; Zhiqi Guan; Tianhao Chu; Yichao Bu; Yi Wang; Fangyu Chen; Jian Zhou; Jia Fan; Zheng Tang; Weiren Liu; Yuanyuan Ruan; Yinghong Shi

doi:10.1002/advs.202408233

Targeting Deltex E3 Ubiquitin Ligase 2 Inhibits Tumor-associated Neutrophils and Sensitizes Hepatocellular Carcinoma Cells to Immunotherapy

Adv Sci (Weinh). 2024 Dec 29:e2408233. doi: 10.1002/advs.202408233. Online ahead of print.

Authors

Xiaoling Wu^{1

2

3}, Jiafeng Chen^{1

2

3}, Yiran Chen^{3

4}, Shushu Song⁵, Yuan Fang^{1

2

3}, Shengwei Mao^{1

2

3}, Jun Gao^{1

2

3}, Guiqi Zhu^{1

2

3}, Weifeng Qu^{1

2

3}, Qianfu Zhao^{1

2

3}, Rui Yang^{1

2

3}, Zhiqi Guan^{1

2

3}, Tianhao Chu^{1

2

3}, Yichao Bu^{1

2

3}, Yi Wang^{1

2

3}, Fangyu Chen⁶, Jian Zhou^{1

2

3

4

7

8

9}, Jia Fan^{1

2

3

4

7

8

9}, Zheng Tang^{1

2

3}, Weiren Liu^{1

2

3}, Yuanyuan Ruan⁵, Yinghong Shi^{1

2

3

8}

Affiliations

¹ Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
² Research Unit of Liver Cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, 100010, China.
³ Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, 200032, China.
⁴ Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
⁵ Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
⁶ Department of Radiation Oncology, Zhongshan Hospital Affiliated to Fudan University, Shanghai, 200032, China.
⁷ Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
⁸ Shanghai Key Laboratory of Organ Transplantation, Shanghai, 200032, China.
⁹ State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, 200032, China.

PMID: 39733452
DOI: 10.1002/advs.202408233

Abstract

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.

Keywords: DTX2 inhibitor; deltex E3 ubiquitin ligase 2; hepatocellular carcinoma; tumor‐associated neutrophils.

Abstract

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