SMAC Mimetic Debio 1143 and Ablative Radiation Therapy Synergize to Enhance Antitumor Immunity against Lung Cancer

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / immunology
  • Apoptosis / radiation effects
  • Apoptosis Regulatory Proteins / metabolism*
  • Azocines / immunology
  • Azocines / therapeutic use*
  • Benzhydryl Compounds / immunology
  • Benzhydryl Compounds / therapeutic use*
  • Biomimetic Materials / metabolism
  • Biomimetic Materials / therapeutic use*
  • 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
  • Carcinoma, Lewis Lung / therapy*
  • Cell Line, Tumor
  • Combined Modality Therapy
  • Cytokines / blood
  • Cytokines / genetics
  • Cytokines / immunology
  • Female
  • Humans
  • Lung Neoplasms / immunology
  • Lung Neoplasms / pathology
  • Lung Neoplasms / therapy*
  • Mice, Inbred C57BL
  • Mitochondrial Proteins / metabolism*
  • Myeloid-Derived Suppressor Cells / immunology
  • Myeloid-Derived Suppressor Cells / metabolism
  • Radiotherapy / methods*
  • 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
  • Azocines
  • Benzhydryl Compounds
  • Cytokines
  • DIABLO protein, human
  • Mitochondrial Proteins
  • N-benzhydryl-5-(2-(methylamino)propanamido)-3-(3-methylbutanoyl)-6-oxodecahydropyrrolo(1,2-a)(1,5)diazocine-8-carboxamide