It is believed that the scope of promising cancer immunotherapy applications is limited because anti-tumor T cells are inhibited in the microenvironment of solid tumors. The overall goal of this proposal is to understand the mechanism of tumor protection and to accomplish the targeted elimination of tumor-protecting immunosuppressive molecules. This is crucial in order to render novel tumor immunotherapies more effective. The central hypothesis of this proposal is that tumor cells in hypoxic cancerous tissues, protected from immune damage because anti-tumor T cells are inactivated by the combined action of at least two hypoxia-dependent mechanisms: (1) extracellular adenosine produced by the hypoxic tumor inhibits T cells via signaling through their surface A2A and A2B adenosine receptors;and (2) the hypoxia-inducible transcription factor 1-alpha (HIF-1alpha) which governs the expression of genes that contribute to the immunosuppressive effects of tumor hypoxia. Our preliminary results - findings of much improved rejection of large tumors in mice with inactivated A2A adenosine receptor - strongly support this hypothesis. Here we plan to further clarify this mechanism of tumor protection by using several recently developed unique mice with T cell-specific deletion of A2A receptor, A2B receptor, and HIF-1alpha genes. Both immunogenic and weakly immunogenic tumors will be tested in different models of CD8+ T cell-mediated rejection by endogenous and adoptively transferred anti-tumor T cells. We expect that targeted deletion of these molecules will render anti-tumor T cells resistant to inhibition in the tumor microenvironment and, thus, facilitate the destruction of tumors. The proposed studies may allow dissection of the complex tumor microenvironment by reducing it to a manageable genetic, immunological, and biochemical analysis of only three molecules - A2A receptor, A2B receptor, and HIF-1alpha- and may also offer a novel and feasible strategy to improve cancer immunotherapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA112561-05
Application #
7563319
Study Section
Special Emphasis Panel (ZRG1-TME (01))
Program Officer
Howcroft, Thomas K
Project Start
2005-03-01
Project End
2011-01-31
Budget Start
2009-02-01
Budget End
2011-01-31
Support Year
5
Fiscal Year
2009
Total Cost
$294,007
Indirect Cost
Name
Northeastern University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
001423631
City
Boston
State
MA
Country
United States
Zip Code
02115
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
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
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
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; 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
Hatfield, Stephen; Belikoff, Bryan; Lukashev, Dmitriy et al. (2009) The antihypoxia-adenosinergic pathogenesis as a result of collateral damage by overactive immune cells. J Leukoc Biol 86:545-8

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