1. SMAC Mimetic Debio 1143 and Ablative Radiation Therapy Synergize to Enhance Antitumor Immunity against Lung Cancer.
- Author
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Tao Z, McCall NS, Wiedemann N, Vuagniaux G, Yuan Z, and Lu B
- Subjects
- Animals, Apoptosis drug effects, Apoptosis immunology, Apoptosis radiation effects, Azocines immunology, Benzhydryl Compounds immunology, Biomimetic Materials metabolism, CD8-Positive T-Lymphocytes drug effects, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes radiation effects, Carcinoma, Lewis Lung immunology, Carcinoma, Lewis Lung pathology, Cell Line, Tumor, Combined Modality Therapy, Cytokines blood, Cytokines genetics, Cytokines immunology, Female, Humans, Lung Neoplasms immunology, Lung Neoplasms pathology, Mice, Inbred C57BL, Myeloid-Derived Suppressor Cells immunology, Myeloid-Derived Suppressor Cells metabolism, T-Lymphocytes, Regulatory drug effects, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory radiation effects, Tumor Microenvironment drug effects, Tumor Microenvironment immunology, Tumor Microenvironment radiation effects, Apoptosis Regulatory Proteins metabolism, Azocines therapeutic use, Benzhydryl Compounds therapeutic use, Biomimetic Materials therapeutic use, Carcinoma, Lewis Lung therapy, Lung Neoplasms therapy, Mitochondrial Proteins metabolism, Radiotherapy methods
- 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., (©2018 American Association for Cancer Research.)- Published
- 2019
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