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  • [Clin Cancer Res.] 폐암에서 SMAC Mimetic Debio 1143과 절제방사선치료가 항암면역을 증진 SMAC Mimetic Debio 1143 and Ablative Radiation Therapy Synergize to Enhance Antitumor Immunity against Lung Cancer.

    Tianjin Medical University Cancer Institute and Hospital / Bo Lu*

  • 출처
    Clin Cancer Res.
  • 등재일
    2019 Feb 1
  • 저널이슈번호
    25(3):1113-1124. doi: 10.1158/1078-0432.CCR-17-3852. Epub 2018 Oct 23.
  • 내용

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    The synergistic mechanism of action between ART and Debio 1143 is illustrated. Left, ART has mixed effects on the immune system. While it increases CD8+ T effector cells and antigen-presenting cells and decreases MDSCs (CD11b+Gr-1+ cells) and Tregs, TAM infiltration, and the production of Arginase-1 and IL10 are also increased. Right, the addition of Debio 1143, a SMAC mimetic, reversed the increases in TAMs, and further reduced infiltration of MDSCs and Tregs within the TME. Furthermore, it reversed the increases in Arginase-1 and IL10 and potentiated the release of TNFα and IFNs as well as the recruitment of antigen-presenting cells compared with ART alone. This coincided with an OVA-specific Tc1 effector antitumor immune response.

    Abstract
    PURPOSE:
    Adaptive antitumor immunity following ablative radiotherapy (ART) is attenuated by host myeloid-derived suppressor cell (MDSC), tumor-associated macrophage (TAM), and regulatory T-cell (Treg) infiltrates. We hypothesized treatment with ART and a secondary mitochondrial-derived activators of caspase (SMAC) mimetic could reverse the immunosuppressive lung cancer microenvironment to favor adaptive immunity.

    EXPERIMENTAL DESIGN:
    To evaluate for synergy between ART and the SMAC mimetic Debio 1143 and the dependence upon CD8+ T cells and TNFα, we used LLC-OVA syngeneic mouse model of lung cancer and treated them with Debio 1143 and/or ART (30 Gy) with or without anti-CD8, anti-TNFα, or anti-IFNγ antibodies. Tumor-infiltrating OVA-specific CD8+ T cells, Tc1 effector cells, MDSCs, TAMs, and Tregs, were quantified by flow cytometry. Tc1-promoting cytokines TNFα, IFNγ, and IL1β and the immunosuppressive IL10 and Arg-1 within LLC-OVA tumor tissue or mouse serum were measured by RT-PCR and ELISA.

    RESULTS:
    ART delayed tumor growth, and the addition of Debio 1143 greatly enhanced its efficacy, which included several complete responses. These complete responders rejected an LLC-OVA tumor rechallenge. ART and Debio 1143 synergistically induced a tumor-specific, Tc1 cellular and cytokine response while eliminating immunosuppressive cells and cytokines from the tumor microenvironment. Depletion of CD8+ cells, TNFα, and IFNγ with blocking antibody abrogated synergy between ART and Debio 1143 and partially restored tumor-infiltrating MDSCs.

    CONCLUSIONS:
    Debio 1143 augments the tumor-specific adaptive immunity induced by ART, while reversing host immunosuppressive cell infiltrates in the tumor microenvironment in a TNFα, IFNγ, and CD8+ T-cell-dependent manner. This provides a novel strategy to enhance the immunogenicity of ART.

     


    Author information

    Tao Z#1, McCall NS#2, Wiedemann N3, Vuagniaux G3, Yuan Z4, Lu B5.
    1
    Department of Radiation Oncology and Cyberknife Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
    2
    Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania.
    3
    Debiopharm International SA, Lausanne, Switzerland.
    4
    Department of Radiation Oncology and Cyberknife Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China. bo.lu@jefferson.edu zhiyong0524@163.com.
    5
    Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania. bo.lu@jefferson.edu zhiyong0524@163.com.
    #
    Contributed equally

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