SMAC mimetic Debio 1143 and ablative radiation therapy synergize to enhance anti-tumor immunity against lung cancer

Purpose: Adaptive anti-tumor immunity following ablative radiation therapy (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 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 TNF-α, we used LLC-OVA syngeneic mouse model of lung cancer and treated them with Debio 1143 and/or ART (30Gy) with or without anti-CD8, anti-TNF-α, or anti-IFN- antibodies. Tumor-infiltrating OVA-specific CD8+ T cells, Tc1 effector cells, MDSCs, TAMs, and Tregs, were quantified by flow cytometry. Tc1-promoting cytokines TNF-α, IFN-, and IL-1β and the immunosuppressive IL-10 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, TNF-α, and IFN- 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 TNF-α, IFN-, and CD8 + T cell-dependent manner. This provides a novel strategy to enhance the immunogenicity of ART

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