2. Academic Validation
  3. Intratumoral injection of mRNA encoding survivin in combination with STAT3 inhibitor stattic enhances antitumor effects

Intratumoral injection of mRNA encoding survivin in combination with STAT3 inhibitor stattic enhances antitumor effects

  • Cancer Lett. 2024 Jul 6:598:217111. doi: 10.1016/j.canlet.2024.217111.
Min Li 1,  Ying Xie 1,  Jincheng Zhang 1,  Xue Zhou 1,  Lei Gao 1,  Mengmeng He 1,  Xianmei Liu 1,  Xinyi Miao 1,  Yu Liu 1,  Rong Cao 1,  Yi Jia 2,  Zhu Zeng 3,  Lina Liu 4
Affiliations

Affiliations

  • 1 Engineering Research Center of Cellular Immunotherapy of Guizhou Province, Key Laboratory of Infectious Immune and Antibody Engineering of Guizhou Province, School of Basic Medical Science/School of Biology and Engineering (School of Health Medicine Modern Industry), Guizhou Medical University, Guiyang, Guizhou, China.
  • 2 Engineering Research Center of Cellular Immunotherapy of Guizhou Province, Key Laboratory of Infectious Immune and Antibody Engineering of Guizhou Province, School of Basic Medical Science/School of Biology and Engineering (School of Health Medicine Modern Industry), Guizhou Medical University, Guiyang, Guizhou, China; Key Laboratory of Biological and Medical Engineering/Immune Cells and Antibody Engineering Research Center of Guizhou Province/Engineering Research Center of Health Medicine Biotechnology of Institution of Higher Education of Guizhou Province, Guizhou Medical University, Guiyang, Guizhou, China. Electronic address: jiayi@gmc.edu.cn.
  • 3 Engineering Research Center of Cellular Immunotherapy of Guizhou Province, Key Laboratory of Infectious Immune and Antibody Engineering of Guizhou Province, School of Basic Medical Science/School of Biology and Engineering (School of Health Medicine Modern Industry), Guizhou Medical University, Guiyang, Guizhou, China; Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, Guizhou, China; Key Laboratory of Biological and Medical Engineering/Immune Cells and Antibody Engineering Research Center of Guizhou Province/Engineering Research Center of Health Medicine Biotechnology of Institution of Higher Education of Guizhou Province, Guizhou Medical University, Guiyang, Guizhou, China. Electronic address: zengzhu@gmc.edu.cn.
  • 4 Engineering Research Center of Cellular Immunotherapy of Guizhou Province, Key Laboratory of Infectious Immune and Antibody Engineering of Guizhou Province, School of Basic Medical Science/School of Biology and Engineering (School of Health Medicine Modern Industry), Guizhou Medical University, Guiyang, Guizhou, China; Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, Guizhou, China; Key Laboratory of Biological and Medical Engineering/Immune Cells and Antibody Engineering Research Center of Guizhou Province/Engineering Research Center of Health Medicine Biotechnology of Institution of Higher Education of Guizhou Province, Guizhou Medical University, Guiyang, Guizhou, China. Electronic address: llngy@gmc.edu.cn.
PMID: 38972347 DOI: 10.1016/j.canlet.2024.217111
Abstract

Intratumoral delivery of mRNA encoding immunostimulatory molecules can initiate a robust, global antitumor response with little side effects by enhancing local antigen presentation in the tumor and the tumor draining lymph node. Neoantigen-based mRNA nanovaccine can inhibit melanoma growth in mice by intratumoral injection. Myeloid-derived suppressor cells (MDSCs) suppress antitumor immune responses by secreting immunosuppressive agents, such as Reactive Oxygen Species (ROS). Suppression of STAT3 activity by stattic may reduce MDSC-mediated immunosuppression in the TME and promote the antitumor immune responses. In this study, in vitro transcribed mRNA encoding tumor antigen Survivin was prepared and injected intratumorally in BALB/c mice bearing subcutaneous colon Cancer tumors. In vivo studies demonstrated that intratumoral Survivin mRNA therapy could induce antitumor T cell response and inhibit tumor growth of colon Cancer. Depletion of CD8+ T cells could significantly inhibit Survivin mRNA-induced antitumor effects. RT-qPCR and ELISA analysis indicated that Survivin mRNA treatment led to increased expression of receptor activator nuclear factor-κB ligand (RANKL). In vitro experiment showed that MDSCs could be induced from mouse bone marrow cells by RANKL and RANKL-induced MDSCs could produce high level of ROS. STAT3 Inhibitor stattic suppressed activation of STAT3 and NF-κB signals, thereby inhibiting expansion of RANKL-induced MDSCs. Combination therapy of Survivin mRNA and stattic could significantly enhance antitumor T cell response, improve long-term survival and reduce immunosuppressive tumor microenvironment compared to each monotherapy. In addition, combined therapy resulted in a significantly reduced level of tumor cell proliferation and an obviously increased level of tumor cell Apoptosis in CT26 colon cancer-bearing mice, which could be conducive to inhibit the tumor growth and lead to immune responses to released tumor-associated antigens. These studies explored intratumoral mRNA therapy and mRNA-based combined therapy to treat colon Cancer and provide a new idea for Cancer therapy.

Keywords

Colon cancer; Combined therapy; Intratumoral mRNA therapy; STAT3 inhibitor stattic.

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Products
  • Cat. No.
    Product Name
    Description
    Target
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  • HY-10172
    99.51%, IKKβ Inhibitor
    IKK