2. Academic Validation
  3. KDM3A Ablation Activates Endogenous Retrovirus Expression to Stimulate Antitumor Immunity in Gastric Cancer

KDM3A Ablation Activates Endogenous Retrovirus Expression to Stimulate Antitumor Immunity in Gastric Cancer

  • Adv Sci (Weinh). 2024 Jul 19:e2309983. doi: 10.1002/advs.202309983.
Jiabin Zheng 1,  Huolun Feng 1 2,  Jiatong Lin 1 2,  Jianlong Zhou 1,  Zhihui Xi 2,  Yucheng Zhang 1,  Fa Ling 1,  Yongfeng Liu 1,  Junjiang Wang 1,  Tieying Hou 3 4,  Fan Xing 5,  Yong Li 1 2
Affiliations

Affiliations

  • 1 Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China.
  • 2 School of Medicine, South China University of Technology, Guangzhou, Guangdong, 510006, China.
  • 3 Medical Experimental Center, Shenzhen Nanshan People's Hospital, Shenzhen, Guangdong, 518052, China.
  • 4 Shenzhen University Medical School, Shenzhen, Guangdong, 518073, China.
  • 5 Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, 510080, China.
PMID: 39031630 DOI: 10.1002/advs.202309983
Abstract

The success of immunotherapy for Cancer treatment is limited by the presence of an immunosuppressive tumor microenvironment (TME); Therefore, identifying novel targets to that can reverse this immunosuppressive TME and enhance immunotherapy efficacy is essential. In this study, enrichment analysis based on publicly available single-cell and bulk RNA Sequencing data from gastric Cancer patients are conducted, and found that tumor-intrinsic interferon (IFN) plays a central role in TME regulation. The results shows that KDM3A over-expression suppresses the tumor-intrinsic IFN response and inhibits KDM3A, either genomically or pharmacologically, which effectively promotes IFN responses by activating endogenous retroviruses (ERVs). KDM3A ablation reconfigures the dsRNA-MAVS-IFN axis by modulating H3K4me2, enhancing the infiltration and function of CD8 T cells, and simultaneously reducing the presence of regulatory T cells, resulting in a reshaped TME in vivo. In addition, combining anti-PD1 therapy with KDM3A inhibition effectively inhibited tumor growth. In conclusions, this study highlights KDM3A as a potential target for TME remodeling and the enhancement of antitumor immunity in gastric Cancer through the regulation of the ERV-MAVS-IFN axis.

Keywords

ERV; KDM3A; gastric cancer; immunotherapy.

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