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Article ; Online: Correction: A2B Adenosine Receptor Expression by Myeloid Cells is Proinflammatory in Murine Allergic-Airway Inflammation.

Belikoff, Bryan G / Vaickus, Louis J / Sitkovsky, Michail / Remick, Daniel G

Journal of immunology (Baltimore, Md. : 1950)

2024 Volume 212, Issue 4, Page(s) 748

Language	English
Publishing date	2024-01-03
Publishing country	United States
Document type	Published Erratum
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.2300855
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Article ; Online: Antihypoxic oxygenation agents with respiratory hyperoxia to improve cancer immunotherapy.

Hatfield, Stephen M / Sitkovsky, Michail V

The Journal of clinical investigation

2020 Volume 130, Issue 11, Page(s) 5629–5637

Abstract: Hypoxia/HIF-1α- and extracellular adenosine/A2 adenosine receptor-mediated immunosuppression protects tissues from collateral damage by antipathogen immune cells. However, this mechanism also protects cancerous tissues by inhibiting antitumor immune ... ...

Abstract	Hypoxia/HIF-1α- and extracellular adenosine/A2 adenosine receptor-mediated immunosuppression protects tissues from collateral damage by antipathogen immune cells. However, this mechanism also protects cancerous tissues by inhibiting antitumor immune cells in hypoxic and extracellular adenosine-rich tumors that are the most resistant to current therapies. Here, we explain a potentially novel, antiimmunosuppressive reasoning to justify strategies using respiratory hyperoxia and oxygenation agents in cancer treatment. Earlier attempts to use oxygenation of tumors as a monotherapy or to improve radiotherapy have failed because oxygenation protocols were not combined with immunotherapies of cancer. In contrast, the proposal for therapeutic use of antihypoxic oxygenation described here was motivated by the need to prevent the hypoxia/HIF-1α-driven accumulation of extracellular adenosine to (a) unleash antitumor immune cells from inhibition by intracellular cAMP and (b) prevent immunosuppressive transcription of cAMP response element- and hypoxia response element-containing immunosuppressive gene products (e.g., TGF-β). Use of oxygenation agents together with inhibitors of the A2A adenosine receptor may be required to enable the most effective cancer immunotherapy. The emerging outcomes of clinical trials of cancer patients refractory to all other treatments provide support for the molecular and immunological mechanism-based approach to cancer immunotherapy described here.
MeSH term(s)	Animals ; Antineoplastic Agents/therapeutic use ; Humans ; Hyperoxia ; Immunotherapy ; Neoplasms/metabolism ; Neoplasms/pathology ; Neoplasms/therapy ; Oxygen/therapeutic use
Chemical Substances	Antineoplastic Agents ; Oxygen (S88TT14065)
Language	English
Publishing date	2020-09-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI137554
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Article ; Online: Adenosine and adenosine receptors in the pathogenesis and treatment of rheumatic diseases.

Cronstein, Bruce N / Sitkovsky, Michail

Nature reviews. Rheumatology

2017 Volume 13, Issue 1, Page(s) 41–51

Abstract: Adenosine, a nucleoside derived primarily from the extracellular hydrolysis of adenine nucleotides, is a potent regulator of inflammation. Adenosine mediates its effects on inflammatory cells by engaging one or more cell-surface receptors. The expression ...

Abstract	Adenosine, a nucleoside derived primarily from the extracellular hydrolysis of adenine nucleotides, is a potent regulator of inflammation. Adenosine mediates its effects on inflammatory cells by engaging one or more cell-surface receptors. The expression and function of adenosine receptors on different cell types change during the course of rheumatic diseases, such as rheumatoid arthritis (RA). Targeting adenosine receptors directly for the treatment of rheumatic diseases is currently under study; however, indirect targeting of adenosine receptors by enhancing adenosine levels at inflamed sites accounts for most of the anti-inflammatory effects of methotrexate, the anchor drug for the treatment of RA. In this Review, we discuss the regulation of extracellular adenosine levels and the role of adenosine in regulating the inflammatory and immune responses in rheumatic diseases such as RA, psoriasis and other types of inflammatory arthritis. In addition, adenosine and its receptors are involved in promoting fibrous matrix production in the skin and other organs, and the role of adenosine in fibrosis and fibrosing diseases is also discussed.
MeSH term(s)	Adaptive Immunity ; Adenosine/immunology ; Adenosine/metabolism ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/pharmacology ; Antirheumatic Agents/pharmacology ; Fibrosis ; Gene Dosage ; Humans ; Immunity, Innate ; Inflammation/metabolism ; Receptor, Adenosine A2A/genetics ; Receptor, Adenosine A2A/metabolism ; Receptors, Purinergic P1/genetics ; Receptors, Purinergic P1/immunology ; Receptors, Purinergic P1/metabolism ; Rheumatic Diseases/drug therapy ; Rheumatic Diseases/immunology ; Rheumatic Diseases/metabolism ; T-Lymphocytes/metabolism
Chemical Substances	Anti-Inflammatory Agents, Non-Steroidal ; Antirheumatic Agents ; Receptor, Adenosine A2A ; Receptors, Purinergic P1 ; Adenosine (K72T3FS567)
Language	English
Publishing date	2017-01
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2491532-4
ISSN	1759-4804 ; 1759-4790
ISSN (online)	1759-4804
ISSN	1759-4790
DOI	10.1038/nrrheum.2016.178
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Article ; Online: A2A adenosine receptor antagonists to weaken the hypoxia-HIF-1α driven immunosuppression and improve immunotherapies of cancer.

Hatfield, Stephen M / Sitkovsky, Michail

Current opinion in pharmacology

2016 Volume 29, Page(s) 90–96

Abstract: Hypoxic and adenosine rich tumor microenvironments represent an important barrier that must be overcome to enable T and NK cells to reject tumors. The A2A adenosine receptor (A2AR) on activated immune cells was identified as a critical and non-redundant ... ...

Abstract	Hypoxic and adenosine rich tumor microenvironments represent an important barrier that must be overcome to enable T and NK cells to reject tumors. The A2A adenosine receptor (A2AR) on activated immune cells was identified as a critical and non-redundant mediator of physiological immunosuppression. Observations showing that tumor-protecting A2AR also suppress and redirect the anti-tumor immune response pointed to the importance of inhibiting this pathway to improve cancer immunotherapy. We advocated (i) blocking immunosuppressive adenosine-A2AR-cAMP-mediated intracellular signaling by A2AR antagonists and (ii) weakening hypoxia-HIF-1α-mediated accumulation of extracellular adenosine by oxygenation agents that also inhibits CD39/CD73 adenosine-generating enzymes. In view of commencing clinical trials of synthetic A2AR antagonists in combination with cancer immunotherapies, we discuss their promise and exclusion criteria.
MeSH term(s)	Adenosine/metabolism ; Adenosine A2 Receptor Antagonists/pharmacology ; Animals ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/immunology ; Immune Tolerance/immunology ; Immunotherapy/methods ; Killer Cells, Natural/immunology ; Neoplasms/drug therapy ; Neoplasms/immunology ; Neoplasms/pathology ; Signal Transduction/immunology ; T-Lymphocytes/immunology ; Tumor Microenvironment/immunology
Chemical Substances	Adenosine A2 Receptor Antagonists ; Hypoxia-Inducible Factor 1, alpha Subunit ; Adenosine (K72T3FS567)
Language	English
Publishing date	2016-08
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2037057-X
ISSN	1471-4973 ; 1471-4892
ISSN (online)	1471-4973
ISSN	1471-4892
DOI	10.1016/j.coph.2016.06.009
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Article: Oxygenation to improve cancer vaccines, adoptive cell transfer and blockade of immunological negative regulators.

Hatfield, Stephen M / Sitkovsky, Michail

Oncoimmunology

2015 Volume 4, Issue 12, Page(s) e1052934

Abstract: Oxygenation of tumors weakens the tumor-protecting immunosuppressive signaling by A2A adenosine receptors in hypoxic and extracellular adenosine-rich microenvironments. This, in turn, unleashes the otherwise inhibited tumor-reactive T and natural killer ( ...

Abstract	Oxygenation of tumors weakens the tumor-protecting immunosuppressive signaling by A2A adenosine receptors in hypoxic and extracellular adenosine-rich microenvironments. This, in turn, unleashes the otherwise inhibited tumor-reactive T and natural killer (NK) cells. Oxygenation of tumors thus emerges as a novel checkpoint inhibitor of potential therapeutic value, but only in combination with cancer immunotherapies.
Language	English
Publishing date	2015-06-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	2645309-5
ISSN	2162-402X ; 2162-4011
ISSN (online)	2162-402X
ISSN	2162-4011
DOI	10.1080/2162402X.2015.1052934
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Article: Mechanistic Justifications of Systemic Therapeutic Oxygenation of Tumors to Weaken the Hypoxia Inducible Factor 1α-Mediated Immunosuppression.

Hatfield, Stephen / Veszeleiova, Katarina / Steingold, Joe / Sethuraman, Jyothi / Sitkovsky, Michail

Advances in experimental medicine and biology

2019 Volume 1136, Page(s) 113–121

Abstract: Long-term studies of anti-pathogen and anti-tumor immunity have provided complementary genetic and pharmacological evidence for the immunosuppressive and immunomodulatory effects of Hypoxia-HIF-1α and adenosine-mediated suppression via the A2A adenosine ... ...

Abstract	Long-term studies of anti-pathogen and anti-tumor immunity have provided complementary genetic and pharmacological evidence for the immunosuppressive and immunomodulatory effects of Hypoxia-HIF-1α and adenosine-mediated suppression via the A2A adenosine receptor signaling pathway (Hypoxia-A2A-adenosinergic). This pathway is life saving when it protects inflamed tissues of vital organs from collateral damage by overactive anti-pathogen immune cells or enables the differentiation of cells of adaptive immunity. However, the Hypoxia-A2A-adenosinergic immunosuppression can also prevent tumor rejection by inhibiting the anti-tumor effects of T and NK cells. In addition, this suppressive pathway has been shown to mask tumors due to the hypoxia-HIF-α-mediated loss of MHC Class I molecules on tumor cells. It is suggested that it will be impossible to realize the full anti-tumor capacities of current cancer immunotherapies without simultaneous administration of anti-Hypoxia-A2A-Adenosinergic drugs that inactivate this tumor-protecting mechanism in hypoxic and adenosine-rich tumors.Here, we overview the supporting evidence for the conceptually novel immunotherapeutic motivation to breathe supplemental oxygen (40-60%) or to repurpose already available oxygenation agents in combination with current immunotherapies. Preclinical studies provide strong support for oxygen immunotherapy to enable much stronger tumor regression by weakening immunosuppression by A2A adenosine receptors and by the Hypoxia➔HIF-1α axis. The results of these studies emphasize the value of systemic oxygenation as clinically feasible, promising, and as a valuable tool for mechanistic investigations of tumor biology and cancer immunology. Perhaps the most effective and feasible among individual members of this novel class of anti-tumor drugs are oxygenation agents.
MeSH term(s)	Cell Hypoxia ; Cell Line, Tumor ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/physiology ; Immune Tolerance ; Immunosuppression ; Neoplasms/pathology ; Receptor, Adenosine A2A/physiology ; Signal Transduction ; Tumor Hypoxia
Chemical Substances	Hypoxia-Inducible Factor 1, alpha Subunit ; Receptor, Adenosine A2A
Language	English
Publishing date	2019-06-14
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-3-030-12734-3_8
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Article: Extracellular adenosine-mediated modulation of regulatory T cells.

Ohta, Akio / Sitkovsky, Michail

Frontiers in immunology

2014 Volume 5, Page(s) 304

Abstract: Extracellular adenosine-dependent suppression and redirection of pro-inflammatory activities are mediated by the signaling through adenosine receptors on the surface of most immune cells. The immunosuppression by endogenously-produced adenosine is ... ...

Abstract	Extracellular adenosine-dependent suppression and redirection of pro-inflammatory activities are mediated by the signaling through adenosine receptors on the surface of most immune cells. The immunosuppression by endogenously-produced adenosine is pathophysiologically significant since inactivation of A2A/A2B adenosine receptor (A2AR/A2BR) and adenosine-producing ecto-enzymes CD39/CD73 results in the higher intensity of immune response and exaggeration of inflammatory damage. Regulatory T cells (Treg) can generate extracellular adenosine, which is implicated in the immunoregulatory activity of Tregs. Interestingly, adenosine has been shown to increase the numbers of Tregs and further promotes their immunoregulatory activity. A2AR-deficiency in Tregs reduces their immunosuppressive efficacy in vivo. Thus, adenosine is not only directly and instantly inhibiting to the immune response through interaction with A2AR/A2BR on the effector cells, but also adenosine signaling can recruit other immunoregulatory mechanisms, including Tregs. Such interaction between adenosine and Tregs suggests the presence of a positive feedback mechanism, which further promotes negative regulation of immune system through the establishment of immunosuppressive microenvironment.
Language	English
Publishing date	2014-07-10
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606827-8
ISSN	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2014.00304
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Article: Oxygen-Generating Cryogels Restore T Cell Mediated Cytotoxicity in Hypoxic Tumors.

Colombani, Thibault / Eggermont, Loek J / Hatfield, Stephen M / Rogers, Zachary J / Rezaeeyazdi, Mahboobeh / Memic, Adnan / Sitkovsky, Michail V / Bencherif, Sidi A

Advanced functional materials

2021 Volume 31, Issue 37

Abstract: Solid tumors are protected from antitumor immune responses due to their hypoxic microenvironments. Weakening hypoxia-driven immunosuppression by hyperoxic breathing of 60% oxygen has shown to be effective in unleashing antitumor immune cells against ... ...

Abstract	Solid tumors are protected from antitumor immune responses due to their hypoxic microenvironments. Weakening hypoxia-driven immunosuppression by hyperoxic breathing of 60% oxygen has shown to be effective in unleashing antitumor immune cells against solid tumors. However, efficacy of systemic oxygenation is limited against solid tumors outside of lungs and has been associated with unwanted side effects. As a result, it is essential to develop targeted oxygenation alternatives to weaken tumor hypoxia as novel approaches to restore immune responses against cancer. Herein, we report on injectable oxygen-generating cryogels (O
Language	English
Publishing date	2021-06-23
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2039420-2
ISSN	1616-3028 ; 1616-301X
ISSN (online)	1616-3028
ISSN	1616-301X
DOI	10.1002/adfm.202102234
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Article ; Online: A

Kjaergaard, Jorgen / Hatfield, Stephen / Jones, Graham / Ohta, Akio / Sitkovsky, Michail

Journal of immunology (Baltimore, Md. : 1950)

2018 Volume 201, Issue 2, Page(s) 782–791

Abstract: Tumor hypoxia-driven accumulation of extracellular adenosine was shown to facilitate tumor evasion by engaging the immunosuppressive, intracellular cAMP-elevating ... ...

Abstract	Tumor hypoxia-driven accumulation of extracellular adenosine was shown to facilitate tumor evasion by engaging the immunosuppressive, intracellular cAMP-elevating A
MeSH term(s)	Adenosine/metabolism ; Adenosine A2 Receptor Antagonists/pharmacology ; Animals ; Brain Neoplasms/immunology ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/transplantation ; Cell Line, Tumor ; Disease Models, Animal ; Female ; Humans ; Hypoxia/immunology ; Immune Tolerance ; Immunity ; Immunotherapy, Adoptive/methods ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Receptor, Adenosine A2A/genetics ; Receptor, Adenosine A2A/metabolism ; Sarcoma/immunology ; Tumor Escape ; Tumor Microenvironment
Chemical Substances	Adenosine A2 Receptor Antagonists ; Receptor, Adenosine A2A ; Adenosine (K72T3FS567)
Language	English
Publishing date	2018-05-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.1700850
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Ud II Zs.37: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Targeting the hypoxia-adenosinergic signaling pathway to improve the adoptive immunotherapy of cancer.

Sitkovsky, Michail / Ohta, Akio

Journal of molecular medicine (Berlin, Germany)

2013 Volume 91, Issue 2, Page(s) 147–155

Abstract: The recent approval by the FDA of cancer vaccines and drugs that blockade immunological negative regulators has further enhanced interest in promising approaches of the immunotherapy of cancer. However, the disappointingly short life extension has also ... ...

Abstract	The recent approval by the FDA of cancer vaccines and drugs that blockade immunological negative regulators has further enhanced interest in promising approaches of the immunotherapy of cancer. However, the disappointingly short life extension has also underscored the need to better understand the mechanisms that prevent tumor rejection and survival even after the blockade of immunological negative regulators. Here, we describe the implications of the "metabolism-based" immunosuppressive mechanism, where the local tissue hypoxia-driven accumulation of extracellular adenosine triggers suppression via A2 adenosine receptors on the surface of activated immune cells. This molecular pathway is of critical importance in mechanisms of immunosuppression in inflamed and cancerous tissue microenvironments. The protection of tumors by tumor-generated extracellular adenosine and A2 adenosine receptors could be the misguided application of the normal tissue-protecting mechanism that limits excessive collateral damage to vital organs during the anti-pathogen immune response. The overview of the current state of the art regarding the immunosuppressive effects of extracellular adenosine is followed by a historical perspective of studies focused on the elucidation of the physiological negative regulators that protect tissues of vital organs from excessive collateral damage, but, as a trade-off, may also weaken the anti-pathogen effector functions and negate the attempts of anti-tumor immune cells to destroy cancerous cells.
MeSH term(s)	Adenosine/immunology ; Animals ; Humans ; Hypoxia/immunology ; Immunotherapy, Adoptive ; Neoplasms/immunology ; Neoplasms/therapy ; Receptors, Adenosine A2/immunology ; Signal Transduction ; T-Lymphocytes/immunology ; Tumor Microenvironment
Chemical Substances	Receptors, Adenosine A2 ; Adenosine (K72T3FS567)
Language	English
Publishing date	2013-01-20
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1223802-8
ISSN	1432-1440 ; 0946-2716
ISSN (online)	1432-1440
ISSN	0946-2716
DOI	10.1007/s00109-013-1001-9
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