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Published on: September 14, 2010
KDM3A Ablation Activates Endogenous Retrovirus Expression to Stimulate Antitumor Immunity in Gastric Cancer
Jiabin Zheng1, Huolun Feng1,2, Jiatong Lin1,2
1Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China.
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.
Insights
Targeting KDM3A reverses immunosuppressive tumor microenvironments by activating interferon responses. This approach enhances CD8 T cell function and improves immunotherapy efficacy in gastric cancer.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Immunotherapy success in cancer is hindered by the immunosuppressive tumor microenvironment (TME).
- Novel therapeutic targets are crucial for reversing TME-induced immunosuppression and boosting immunotherapy.
- Tumor-intrinsic interferon (IFN) signaling is a key regulator of the TME.
Purpose of the Study:
- To identify novel targets for reversing the immunosuppressive TME.
- To investigate the role of KDM3A in regulating tumor-intrinsic IFN responses.
- To evaluate KDM3A inhibition as a strategy to enhance anti-tumor immunity and immunotherapy.
Main Methods:
- Enrichment analysis of single-cell and bulk RNA sequencing data from gastric cancer patients.
- Genomic and pharmacological inhibition of KDM3A.
- Assessment of the dsRNA-MAVS-IFN axis and H3K4me2 modulation.
- Evaluation of CD8 T cell infiltration and regulatory T cell populations in vivo.
- Combination therapy with anti-PD1 and KDM3A inhibition.
Main Results:
- KDM3A overexpression suppresses tumor-intrinsic IFN responses.
- KDM3A inhibition activates endogenous retroviruses (ERVs) and promotes IFN responses.
- KDM3A ablation reconfigures the dsRNA-MAVS-IFN axis, enhancing CD8 T cell function and reducing regulatory T cells.
- Combined anti-PD1 therapy and KDM3A inhibition significantly inhibited tumor growth.
Conclusions:
- KDM3A is a critical regulator of the TME and IFN responses in gastric cancer.
- Inhibiting KDM3A reshapes the TME by modulating the ERV-MAVS-IFN axis.
- KDM3A inhibition represents a promising strategy to enhance anti-tumor immunity and immunotherapy efficacy.
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