SMAC Mimetic Debio 1143 and Ablative Radiation Therapy Synergize to Enhance Antitumor Immunity against Lung Cancer.
Clin Cancer Res
; 25(3): 1113-1124, 2019 02 01.
Article
en En
| MEDLINE
| ID: mdl-30352911
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 IL1ß 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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Radioterapia
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Azocinas
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Compuestos de Bencidrilo
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Carcinoma Pulmonar de Lewis
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Proteínas Mitocondriales
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Materiales Biomiméticos
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Proteínas Reguladoras de la Apoptosis
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Neoplasias Pulmonares
Tipo de estudio:
Prognostic_studies
Límite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Clin Cancer Res
Asunto de la revista:
NEOPLASIAS
Año:
2019
Tipo del documento:
Article
País de afiliación:
China
Pais de publicación:
Estados Unidos