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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.
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Contributed equally