{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T18:18:08Z","timestamp":1772302688578,"version":"3.50.1"},"reference-count":60,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2023,5,17]],"date-time":"2023-05-17T00:00:00Z","timestamp":1684281600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 CA248741"],"award-info":[{"award-number":["R01 CA248741"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 CA175370"],"award-info":[{"award-number":["R01 CA175370"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 CA138923"],"award-info":[{"award-number":["R01 CA138923"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Meharry Clinical and Translational Research Center Pilot","award":["U54 MD007593"],"award-info":[{"award-number":["U54 MD007593"]}]},{"name":"Meharry Clinical and Translational Research Center Pilot","award":["U54 CA163069"],"award-info":[{"award-number":["U54 CA163069"]}]},{"name":"Meharry Clinical and Translational Research Center Pilot","award":["SC1 CA182843"],"award-info":[{"award-number":["SC1 CA182843"]}]},{"name":"Meharry Clinical and Translational Research Center Pilot","award":["R01 CA 149013"],"award-info":[{"award-number":["R01 CA 149013"]}]},{"name":"Meharry Clinical and Translational Research Center Pilot","award":["CA192064"],"award-info":[{"award-number":["CA192064"]}]},{"name":"OSU K12 Training Grant for Clinical Investigators","award":["K12 CA133250"],"award-info":[{"award-number":["K12 CA133250"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,11,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>We investigated the role of A2B-adenosine receptor in regulating immunosuppressive metabolic stress in the tumor microenvironment. Novel A2B-adenosine receptor antagonist PBF-1129 was tested for antitumor activity in mice and evaluated for safety and immunologic efficacy in a phase I clinical trial of patients with non-small cell lung cancer.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>The antitumor efficacy of A2B-adenosine receptor antagonists and their impact on the metabolic and immune tumor microenvironment were evaluated in lung, melanoma, colon, breast, and epidermal growth factor receptor\u2013inducible transgenic cancer models. Employing electron paramagnetic resonance, we assessed changes in tumor microenvironment metabolic parameters, including pO2, pH, and inorganic phosphate, during tumor growth and evaluated the immunologic effects of PBF-1129, including its pharmacokinetics, safety, and toxicity, in patients with non-small cell lung cancer.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Levels of metabolic stress correlated with tumor growth, metastasis, and immunosuppression. Tumor interstitial inorganic phosphate emerged as a correlative and cumulative measure of tumor microenvironment stress and immunosuppression. A2B-adenosine receptor inhibition alleviated metabolic stress, downregulated expression of adenosine-generating ectonucleotidases, increased expression of adenosine deaminase, decreased tumor growth and metastasis, increased interferon \u03b3 production, and enhanced the efficacy of antitumor therapies following combination regimens in animal models (anti\u2013programmed cell death 1 protein vs anti\u2013programmed cell death 1 protein plus PBF-1129 treatment hazard ratio = 11.74 [95% confidence interval\u2009=\u20093.35 to 41.13], n\u2009=\u200910, P\u2009&amp;lt;\u2009.001, 2-sided F test). In patients with non-small cell lung cancer, PBF-1129 was well tolerated, with no dose-limiting toxicities; demonstrated pharmacologic efficacy; modulated the adenosine generation system; and improved antitumor immunity.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Data identify A2B-adenosine receptor as a valuable therapeutic target to modify metabolic and immune tumor microenvironment to reduce immunosuppression, enhance the efficacy of immunotherapies, and support clinical application of PBF-1129 in combination therapies.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jnci\/djad091","type":"journal-article","created":{"date-parts":[[2023,5,17]],"date-time":"2023-05-17T15:03:08Z","timestamp":1684335788000},"page":"1404-1419","source":"Crossref","is-referenced-by-count":25,"title":["Improving combination therapies: targeting A2B-adenosine receptor to modulate metabolic tumor microenvironment and immunosuppression"],"prefix":"10.1093","volume":"115","author":[{"given":"Jason V","family":"Evans","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, The James Comprehensive Cancer Center, The Ohio State University , Columbus, OH, USA"},{"name":"Department of Pathology, Anatomy, and Laboratory Medicine, School of Medicine, West Virginia University , Morgantown, WV, USA"}]},{"given":"Shankar","family":"Suman","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, The James Comprehensive Cancer Center, The Ohio State University , Columbus, OH, USA"}]},{"given":"Mounika Uttam L","family":"Goruganthu","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, The James Comprehensive Cancer Center, The Ohio State University , Columbus, OH, USA"}]},{"given":"Elena E","family":"Tchekneva","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, The James Comprehensive Cancer Center, The Ohio State University , Columbus, OH, USA"}]},{"given":"Shuxiao","family":"Guan","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, The James Comprehensive Cancer Center, The Ohio State University , Columbus, OH, USA"}]},{"given":"Rajeswara Rao","family":"Arasada","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, The James Comprehensive Cancer Center, The Ohio State University , Columbus, OH, USA"},{"name":"Pfizer Inc , New York, NY, USA"}]},{"given":"Anneliese","family":"Antonucci","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, The James Comprehensive Cancer Center, The Ohio State University , Columbus, OH, USA"}]},{"given":"Longzhu","family":"Piao","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, The James Comprehensive Cancer Center, The Ohio State University , Columbus, OH, USA"}]},{"given":"Irina","family":"Ilgisonis","sequence":"additional","affiliation":[{"name":"N.V. Sklifosovsky Institute of Clinical Medicine, I.M. Sechenov First Moscow State Medical University , Moscow, Russia"}]},{"given":"Andrey A","family":"Bobko","sequence":"additional","affiliation":[{"name":"In Vivo Multifunctional Magnetic Resonance Center, West Virginia University , Morgantown, WV, USA"},{"name":"Department of Biochemistry, West Virginia University , Morgantown, WV, USA"}]},{"given":"Benoit","family":"Driesschaert","sequence":"additional","affiliation":[{"name":"In Vivo Multifunctional Magnetic Resonance Center, West Virginia University , Morgantown, WV, USA"},{"name":"Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University , Morgantown, WV, USA"}]},{"given":"Roman V","family":"Uzhachenko","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, School of Medicine, Meharry Medical College , Nashville, TN, USA"},{"name":"Department of Pathology, The Ohio State University Wexner Medical Center , Columbus, OH, USA"}]},{"given":"Rebecca","family":"Hoyd","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, The James Comprehensive Cancer Center, The Ohio State University , Columbus, OH, USA"}]},{"given":"Alexandre","family":"Samouilov","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, The James Comprehensive Cancer Center, The Ohio State University , Columbus, OH, USA"}]},{"given":"Joseph","family":"Amann","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, The James Comprehensive Cancer Center, The Ohio State University , Columbus, OH, USA"}]},{"given":"Ruohan","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, The James Comprehensive Cancer Center, The Ohio State University , Columbus, OH, USA"}]},{"given":"Lai","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, The James Comprehensive Cancer Center, The Ohio State University , Columbus, OH, USA"}]},{"given":"Aaditya","family":"Pallerla","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, The James Comprehensive Cancer Center, The Ohio State University , Columbus, OH, USA"}]},{"given":"Sergey V","family":"Ryzhov","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine, Maine Medical Center Research Institute , Scarborough, ME, USA"}]},{"given":"Igor","family":"Feoktistov","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University , Nashville, TN, USA"}]},{"given":"Kyungho P","family":"Park","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University , Nashville, TN, USA"}]},{"given":"Takefumi","family":"Kikuchi","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Department of Internal Medicine, Sapporo Shirakabadai Hospital , Sapporo, Japan"}]},{"given":"Julio","family":"Castro","sequence":"additional","affiliation":[{"name":"Palobiofarma SL , Barcelona, Spain"}]},{"given":"Alla V","family":"Ivanova","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, School of Medicine, Meharry Medical College , Nashville, TN, USA"},{"name":"School of Graduate Studies, Meharry Medical College , Nashville, TN, USA"}]},{"given":"Thanigaivelan","family":"Kanagasabai","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, School of Medicine, Meharry Medical College , Nashville, TN, USA"},{"name":"School of Graduate Studies, Meharry Medical College , Nashville, TN, USA"}]},{"given":"Dwight H","family":"Owen","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, The James Comprehensive Cancer Center, The Ohio State University , Columbus, OH, USA"}]},{"given":"Daniel J","family":"Spakowicz","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, The James Comprehensive Cancer Center, The Ohio State University , Columbus, OH, USA"}]},{"given":"Jay L","family":"Zweier","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, The James Comprehensive Cancer Center, The Ohio State University , Columbus, OH, USA"}]},{"given":"David P","family":"Carbone","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, The James Comprehensive Cancer Center, The Ohio State University , Columbus, OH, USA"}]},{"given":"Sergey V","family":"Novitskiy","sequence":"additional","affiliation":[{"name":"Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University , Nashville, TN, USA"}]},{"given":"Valery V","family":"Khramtsov","sequence":"additional","affiliation":[{"name":"In Vivo Multifunctional Magnetic Resonance Center, West Virginia University , Morgantown, WV, USA"},{"name":"Department of Biochemistry, West Virginia University , Morgantown, WV, USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6372-3669","authenticated-orcid":false,"given":"Anil","family":"Shanker","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, School of Medicine, Meharry Medical College , Nashville, TN, USA"},{"name":"School of Graduate Studies, Meharry Medical College , Nashville, TN, USA"},{"name":"Vanderbilt-Ingram Cancer Center, Vanderbilt University , Nashville, TN, USA"},{"name":"V , Nashville, TN, USA"},{"name":"anderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt University , Nashville, TN, USA"}]},{"given":"Mikhail M","family":"Dikov","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, The James Comprehensive Cancer Center, The Ohio State University , Columbus, OH, 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