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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA111985-07
Application #
8464014
Study Section
Special Emphasis Panel (ZRG1-OTC-Y (02))
Program Officer
Muszynski, Karen
Project Start
2005-01-01
Project End
2017-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
7
Fiscal Year
2013
Total Cost
$201,543
Indirect Cost
$71,934
Name
Northeastern University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
001423631
City
Boston
State
MA
Country
United States
Zip Code
02115
Sitkovsky, Michail V; Hatfield, Stephen; Abbott, Robert et al. (2014) Hostile, hypoxia-A2-adenosinergic tumor biology as the next barrier to overcome for tumor immunologists. Cancer Immunol Res 2:598-605
Ohta, Akio; Madasu, Manasa; Subramanian, Meenakshi et al. (2014) Hypoxia-induced and A2A adenosine receptor-independent T-cell suppression is short lived and easily reversible. Int Immunol 26:83-91
Subramanian, Meenakshi; Kini, Radhika; Madasu, Manasa et al. (2014) Extracellular adenosine controls NKT-cell-dependent hepatitis induction. Eur J Immunol 44:1119-29
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
Sitkovsky, Michail; Ohta, Akio (2013) Targeting the hypoxia-adenosinergic signaling pathway to improve the adoptive immunotherapy of cancer. J Mol Med (Berl) 91:147-55
Kojima, Hidefumi; Kobayashi, Ayano; Sakurai, Daisuke et al. (2010) Differentiation stage-specific requirement in hypoxia-inducible factor-1alpha-regulated glycolytic pathway during murine B cell development in bone marrow. J Immunol 184:154-63
Moriyama, Kengo; Sitkovsky, Michail V (2010) Adenosine A2A receptor is involved in cell surface expression of A2B receptor. J Biol Chem 285:39271-88
Ohta, Akio; Sitkovsky, Michail (2009) The adenosinergic immunomodulatory drugs. Curr Opin Pharmacol 9:501-6
Ohta, Akio; Ohta, Akiko; Madasu, Manasa et al. (2009) A2A adenosine receptor may allow expansion of T cells lacking effector functions in extracellular adenosine-rich microenvironments. J Immunol 183:5487-93
Ohta, Akio; Kjaergaard, J; Sharma, S et al. (2009) In vitro induction of T cells that are resistant to A2 adenosine receptor-mediated immunosuppression. Br J Pharmacol 156:297-306

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