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• W2953702986 abstract "Abstract Adenosine signaling is a normal physiologic process preventing autoimmunity, that is co-opted by tumors as an immune escape mechanism. Dendritic cells (DC), generated from human monocytes or mouse bone marrow, are susceptible to the immunosuppressive effects of extracellular adenosine. In vitro studies using a stable analog of adenosine, 5’-N-ethylcarboxamidoadenosine (NECA), demonstrate DC dysfunction in differentiation and of priming naïve T cells. This negatively effects the critical role of DCs to drive antigen-specific tumor cytotoxic T cell responses under conditions of high extracellular adenosine. AZD4635 (HTL-1071) is a selective oral A2AR antagonist, currently in clinical trials as a single agent and in combination with durvalumab (anti-PD-L1 Ab) in patients with solid malignancies. We have reported previously that AZD4635 treatment led to reduction in tumor growth as monotherapy and in combination with anti-PD-L1 Ab in several syngeneic mouse tumor models. Antitumor activity by AZD4635 was supported by the observation that AZD4635 treated tumors had increased expression of genes associated with immune activation and increased expression of co-stimulatory molecules on antigen presenting cells (APCs). We now extend our previous findings by demonstrating improved antigen presentation in antigen-specific mouse (OVA) and human (Melan-A) systems and show reversed dysfunction in mouse CD103+ crosspresenting/crosspriming DC. In this report, we tested the ability of AZD4635 to prevent adenosine-mediated immunosuppression of antigen specific responses in both mouse and human DCs. We demonstrate that AZD4635 could significantly prevent NECA-mediated immuno-suppression of critical aspects of CD103+ DC phenotype and function in vitro. These included CD103+ DC differentiation and costimulatory molecule expression in FLT-3L/GM-CSF differentiated mouse bone marrow cultures, reduced pinocytosis of ovalbumin and subsequently reduced antigen processing and presentation, leading to weaker OT-I T cell functional responses in vitro. NECA also affected the ability of CD103+ DC to crosspresent antigens from dying MC38-Ova tumor cells and crossprime OT-I T cells in vitro. In vivo, immunophenotyping showed that mice bearing MC38-OVA tumors treated with AZD4635 and anti-PD-L1 had increased antigen-specific T cells and CD103+ DC in tumors. CD103+ DC from TdLN of AZD4635 treated mice elicited proliferation of OT-I T cells without exogenously added antigen. In co-cultures of naïve human CD8+ T cells and DCs containing an HLA-A2-restricted Melan-A peptide, NECA abrogated the ability of monocyte-derived DC to prime antigen specific CD8+ T cells. Adenosine antagonism by AZD4635 improved antigen presentation and costimulation by DCs, leading to better priming and expansion of antigen specific T cells. In summary, we report that AZD4635’s MOA includes restoration of DC function in the elicitation of antigen-specific T cell responses. Citation Format: Christine M. Barbon, Alexandra Borodovsky, Yanjun Wang, Laura Prickett, Kris Sachsenmeier, Alwin Schuller, Wenlin Shao, Carl Barrett, Stephen Fawell, Deanna A. Mele. The A2AR antagonist AZD4635 prevents adenosine-mediated immunosuppression of CD103+ dendritic cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-192." @default.
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• W2953702986 date "2019-07-01" @default.
• W2953702986 modified "2023-09-26" @default.
• W2953702986 title "Abstract LB-192: The A2AR antagonist AZD4635 prevents adenosine-mediated immunosuppression of CD103+ dendritic cells" @default.
• W2953702986 doi "https://doi.org/10.1158/1538-7445.am2019-lb-192" @default.
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