1RO1 CA111985-01 Title: Cancer immunotherapy by targeting A2 adenosine receptor. It is believed that cancer immunotherapy applications are limited because anti-tumor T cells are inhibited in the immunosuppressive microenvironment of solid tumors. The overall goal of this proposal is to render cancer immunotherapies more effective by inactivating mechanisms that inhibit anti-tumor T cells near or within tumors. The central hypothesis of this proposal is that genetic deletion or pharmacological inactivation of immunosuppressive, Gs protein coupled A2 adenosine receptor subtypes A2A and A2B (A2AR and A2BR, respectively) should prevent the inhibition of anti-tumor T cells and thus facilitate their complete rejection. This hypothesis was prompted by our earlier findings that A2AR and A2BR play a critical role in the protection of normal tissues (e.g., liver and lung) from overactive immune cells in acutely inflamed and hypoxic areas. Our preliminary results confirmed this hypothesis by demonstrating the complete or much improved rejection of large tumors in -60%mice with genetically inactivated A2AR. Our data strongly suggest that both A2AR and A2BR should be inactivated in order to eliminate tumor protection in 100% of mice. Here we propose to take advantage of this new understanding to accomplish the complete rejection of tumors by making anti-tumor T cells resistant to inhibition by tumor-produced adenosine. This will be done via genetic deletion of both A2AR and A2BR in mice, or by treatments of tumor-bearing mice with novel antagonists selective for both A2AR and A2BR or by negative selection of """"""""inhibitable"""""""" anti-tumor T cells during expansion in vitro. Unique types of mice-deficient in A2AR or A2BR or both?will be used to test this novel and feasible strategy to improve the immunotherapy of cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Cancer Immunopathology and Immunotherapy Study Section (CII)
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Muszynski, Karen
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Northeastern University
Schools of Pharmacy
United States
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Yuan, Gengyang; Jankins, Tanner C; Patrick Jr, Christopher G et al. (2017) Fluorinated Adenosine A2A Receptor Antagonists Inspired by Preladenant as Potential Cancer Immunotherapeutics. Int J Med Chem 2017:4852537
Silva, Murillo; Nguyen, Thao H; Philbrook, Phaethon et al. (2017) Targeted Elimination of Immunodominant B Cells Drives the Germinal Center Reaction toward Subdominant Epitopes. Cell Rep 21:3672-3680
Abbott, Robert K; Silva, Murillo; Labuda, Jasmine et al. (2017) The GS Protein-coupled A2a Adenosine Receptor Controls T Cell Help in the Germinal Center. J Biol Chem 292:1211-1217
Cronstein, Bruce N; Sitkovsky, Michail (2017) Adenosine and adenosine receptors in the pathogenesis and treatment of rheumatic diseases. Nat Rev Rheumatol 13:41-51
Hatfield, Stephen M; Sitkovsky, Michail (2016) A2A adenosine receptor antagonists to weaken the hypoxia-HIF-1? driven immunosuppression and improve immunotherapies of cancer. Curr Opin Pharmacol 29:90-6
Abbott, Robert K; Thayer, Molly; Labuda, Jasmine et al. (2016) Germinal Center Hypoxia Potentiates Immunoglobulin Class Switch Recombination. J Immunol 197:4014-4020
Hatfield, Stephen M; Sitkovsky, Michail (2015) Oxygenation to improve cancer vaccines, adoptive cell transfer and blockade of immunological negative regulators. Oncoimmunology 4:e1052934
Hatfield, Stephen M; Kjaergaard, Jorgen; Lukashev, Dmitriy et al. (2015) Immunological mechanisms of the antitumor effects of supplemental oxygenation. Sci Transl Med 7:277ra30
Hatfield, Stephen M; Kjaergaard, Jorgen; Lukashev, Dmitriy et al. (2014) Systemic oxygenation weakens the hypoxia and hypoxia inducible factor 1?-dependent and extracellular adenosine-mediated tumor protection. J Mol Med (Berl) 92:1283-92
Subramanian, Meenakshi; Kini, Radhika; Madasu, Manasa et al. (2014) Extracellular adenosine controls NKT-cell-dependent hepatitis induction. Eur J Immunol 44:1119-29

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