The overarching goal of this proposal is to provide the molecular mechanistic understanding of hypoxia- adenosinergic immunosuppression in the tumor microenvironment (TME). This research is important as part of fundamental cancer immunology studies and for the development of promising, novel anti-hypoxia- adenosinergic immunotherapy. These protocols require continuous improvement and optimization to assist current translation into the clinic. The proposed research will investigate molecular and cellular events that are controlled by immunosuppressive A2A adenosine receptors (A2AR) on the surface of tumor-reactive T cells. Preventing A2AR-mediated inhibition of tumor-reactive T cells may be critical for enabling tumor rejection. In our studies so far, it was established that it is the tumor hypoxia-produced extracellular adenosine and the A2AR adenosine receptor-mediated elevation of immunosuppressive intracellular cAMP that inhibit anti-tumor T-lymphocytes. It was demonstrated that either A2AR genetic targeting or A2AR antagonists prevent inhibition of T cells and enable tumor rejection and survival. This led to considerations of novel methods to lower levels of tumor-produced adenosine and A2AR signaling. To this end, we tested and confirmed the conceptually novel medical use of supplemental oxygen (40-60%) to prevent accumulation of immunosuppressive extracellular adenosine in the TME. Our observations stimulated clinician-scientists in the USA and Russia to combine their existing immunotherapy protocols of cancer patients with 40% or 60% oxygen breathing and treatment with the natural A2AR antagonist theophylline.
The aims of this proposal are to establish the role of the hypoxia-A2AR-adenosinergic pathway in molecular and cellular mechanisms of tumor rejection by cancer vaccine-induced tumor-reactive T cells and by adoptively transferred tumor-reactive T cells. In our new Aim 1, we will investigate the extent by which physiological immunosuppression of anti-tumor immunity by A2AR collaborates with and/or controls immunological negative regulators.
In Aims 2, 3, we will establish the upper limit of anti-A2AR-adenosinergic anti-tumor treatment in combination with cancer vaccines and CTLA-4 antibody blockade and clarify the molecular and immunological consequences of targeting A2AR on tumor-reactive T cells and myeloid cells. It is expected that these studies will determine how hypoxia-A2AR-adenosinergic immunosuppression prevents tumor rejection and enables survival and long-term immunological memory against rejected tumors. This, in turn, will provide superior design of anti-hypoxia-A2AR-adenosinergic clinical protocols.
In this study, we are using mouse cancer models to develop a novel cancer therapy that improves the ability of the immune system to destroy tumors. This therapy acts by deactivating the tumor's protective mechanism thereby enabling the body's immune system to kill the tumor. The hope is that, used in conjunction with the person's ongoing cancer treatment, this therapy may eventually improve rejection of the tumor, increase survival, and create an immunological memory in the patient's body to protect it from cancer recurrence. It is anticipated that this immunotherapy will increase the effectiveness of current cancer treatments and decrease morbidity and mortality in several forms of cancer.
|Kjaergaard, Jorgen; Hatfield, Stephen; Jones, Graham et al. (2018) A2A Adenosine Receptor Gene Deletion or Synthetic A2A Antagonist Liberate Tumor-Reactive CD8+ T Cells from Tumor-Induced Immunosuppression. J Immunol 201:782-791|
|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|
|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|
|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; 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 (2016) A2A adenosine receptor antagonists to weaken the hypoxia-HIF-1? driven immunosuppression and improve immunotherapies of cancer. Curr Opin Pharmacol 29:90-6|
|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|
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