50 results match your criteria: "New England Inflammation and Tissue Protection Institute[Affiliation]"

Article Synopsis
  • Recurrent ovarian cancer patients, especially those resistant to platinum treatments, currently have few effective curative options, prompting a phase 2 clinical trial (NCT02853318) that combined pembrolizumab with bevacizumab and oral cyclophosphamide.
  • The trial included 40 patients and showed promising results, with a median progression-free survival of 10.2 months, a 47.5% objective response rate, and 30% of patients achieving stable disease for over a year while maintaining a good quality of life.
  • Comprehensive analysis revealed that increased T and B cell count and specific microbiome patterns correlated with strong clinical responses, suggesting that understanding the immune environment and gut microbiome could enhance future cancer treatment
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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.

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Therapeutic Targeting of Hypoxia-A2-Adenosinergic Pathway in COVID-19 Patients.

Physiology (Bethesda)

January 2022

New England Inflammation and Tissue Protection Institute, Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts.

The hypoxia-hypoxia-inducible factor (HIF)-1α-A2-adenosinergic pathway protects tissues from inflammatory damage during antipathogen immune responses. The elimination of this physiological tissue-protecting mechanism by supplemental oxygenation may contribute to the high mortality of oxygen-ventilated COVID-19 patients by exacerbating inflammatory lung damage. Restoration of this pathway with hypoxia-adenosinergic drugs may improve outcomes in these patients.

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Case Report: Can Inhaled Adenosine Attenuate COVID-19?

Front Pharmacol

August 2021

Department of Community Health and Family Medicine, University of Florida, College of Medicine, Gainesville, FL, United States.

This case report demonstrates a small repetition of the case series carried out in Italy wherein inhaled adenosine was administered to patients experiencing severe and worsening coronavirus disease-2019 (COVID-19). The two cases are important not only because they were the first of their type in the United States, but also because both patients were DNR/DNI and were therefore expected to die. Study repetition is vitally important in medicine.

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Editorial overview: Cancer 2020 current mechanistic insights into the hypoxia-adenosine-A2A adenosinergic immunosuppressive axis in cancer immunotherapies.

Curr Opin Pharmacol

August 2020

New England Inflammation and Tissue Protection Institute, Department of Pharmaceutical Sciences, Bouvé College of Health Sciences, Northeastern University, Boston, MA 02115, United States.

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Targeting Hypoxia-A2A Adenosinergic Immunosuppression of Antitumor T Cells During Cancer Immunotherapy.

Front Immunol

May 2021

Department of Pharmaceutical Sciences, New England Inflammation and Tissue Protection Institute, Bouvé College of Health Sciences, Northeastern University, Boston, MA, United States.

The blockade of immunological negative regulators offered a novel therapeutic approach that revolutionized the immunotherapy of cancer. Still, a significant portion of patients fail to respond to anti-PD-1/PD-L1 and/or anti-CTLA-4 therapy or experience significant adverse effects. We propose that one of the major reasons that many patients do not respond to this form of therapy is due to the powerful physiological suppression mediated by hypoxia-adenosinergic signaling.

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Background: SARS-Cov2 infection may trigger lung inflammation and acute-respiratory-distress-syndrome (ARDS) that requires active ventilation and may have fatal outcome. Considering the severity of the disease and the lack of active treatments, 14 patients with Covid-19 and severe lung inflammation received inhaled adenosine in the attempt to therapeutically compensate for the oxygen-related loss of the endogenous adenosine→A2A adenosine receptor (A2AR)-mediated mitigation of the lung-destructing inflammatory damage. This off label-treatment was based on preclinical studies in mice with LPS-induced ARDS, where inhaled adenosine/A2AR agonists protected oxygenated lungs from the deadly inflammatory damage.

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Sufficient numbers of anti-tumor T cells is a condition of maximal efficacy of anti-hypoxia-A2-adenosinergic drugs during cancer immunotherapy.

Curr Opin Pharmacol

August 2020

New England Inflammation and Tissue Protection Institute, Department of Pharmaceutical Sciences and Biology, Northeastern University, Boston, MA 02115, United States. Electronic address:

The anti-hypoxia-A2-Adenosinergic immunotherapies of cancer emerged as the only available now approach to enable the tumor rejection in those progressing cancer patients that are refractory to all other current treatments. Several different classes of drugs are offered to inhibit the Hypoxia-HIF-1alpha-mediated and extracellular adenosine-A2A adenosine receptor-mediated immunosuppressive signaling in tumor microenvironment. It is suggested that the most promising treatments must include the blockade of cAMP-elevating A2A adenosine receptors and the elimination of hypoxia in tumors by oxygenation agents and hyperoxic breathing.

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Oxygenation and A2AR blockade to eliminate hypoxia/HIF-1α-adenosinergic immunosuppressive axis and improve cancer immunotherapy.

Curr Opin Pharmacol

August 2020

New England Inflammation and Tissue Protection Institute, Department of Pharmaceutical Sciences, Bouvé College of Health Sciences, Northeastern University, Boston, MA 02115, United States. Electronic address:

The promising results of the first in-human clinical study using A2AR antagonists for treatment of renal cell carcinoma highlight two decades of research into the hypoxia-A2-adenosinergic pathway. Importantly, clinical responses have been observed in patients who previously progressed on anti-PD-1/PDL-1 therapy, emphasizing the clinical importance of targeting A2AR signaling in cancer immunotherapies. Recently, it has been shown that systemic oxygenation weakens all known stages of the hypoxia-A2-adenosinergic axis.

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In this issue of , Fong and colleagues describe the encouraging observations of tumor regression, disease control, and survival of patients with otherwise refractory renal cell cancer with progressive disease after treatment with the conceptually novel oral antagonist of the A2A adenosine receptor (A2AR), ciforadenant. A2AR antagonists may represent the until now missing but critically important part of more effective immunotherapies of cancer, because they prevent the inhibition of tumor-reactive T and natural killer cells by blocking the immunosuppressive hypoxia-A2A-adenosinergic signaling, which represents an emerging immunosuppressive hallmark of tumors that are the most resistant to therapies..

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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.

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Article Synopsis
  • - Tumor hypoxia causes the buildup of extracellular adenosine, which activates A adenosine receptors (AR) on CD8 T cells, leading to immunosuppression and enabling tumor evasion of the immune system.
  • - Research showed that deleting AR genes in mice restored CD8 T cell anti-tumor activity against less immunogenic tumors, and using AR antagonists in adoptive T cell therapy achieved similar results, suggesting a method to enhance T cell responses.
  • - Targeting AR improved survival rates and established long-lasting anti-tumor immunity, highlighting both the suppressive role of AR in tumor environments and the potential of selective antagonists to enhance the effectiveness of current immunotherapy approaches.
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Rapidly evolving pathogens such as HIV or influenza can quickly mutate their antigenic profiles, reducing the efficacy of conventional vaccines. Despite this challenge, functionally required epitopes are highly conserved among heterologous viral strains and represent a key vulnerability that could be targeted during vaccine development. As the antigenicity of these conserved epitopes is frequently subdominant, there is a critical need for innovative vaccination strategies designed to target these neutralizing epitopes.

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Human cancers are known to downregulate Major Histocompatibility Complex (MHC) class I expression thereby escaping recognition and rejection by anti-tumor T cells. Here we report that oxygen tension in the tumor microenvironment (TME) serves as an extrinsic cue that regulates antigen presentation by MHC class I molecules. In support of this view, hypoxia is shown to negatively regulate MHC expression in a HIF-dependent manner as evidenced by (i) lower MHC expression in the hypoxic TME in vivo and in hypoxic 3-dimensional (3D) but not 2-dimensional (2D) tumor cell cultures in vitro; (ii) decreased MHC in human renal cell carcinomas with constitutive expression of HIF due to genetic loss of von Hippel-Lindau (VHL) function as compared with isogenically paired cells with restored VHL function, and iii) increased MHC in tumor cells with siRNA-mediated knockdown of HIF.

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The GS Protein-coupled A2a Adenosine Receptor Controls T Cell Help in the Germinal Center.

J Biol Chem

January 2017

From the New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, Massachusetts 02115 and

T follicular helper (T) cells have been shown to be critically required for the germinal center (GC) reaction where B cells undergo class switch recombination and clonal selection to generate high affinity neutralizing antibodies. However, detailed knowledge of the physiological cues within the GC microenvironment that regulate T cell help is limited. The cAMP-elevating, G protein-coupled A2a adenosine receptor (A2aR) is an evolutionarily conserved receptor that limits and redirects cellular immunity.

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Adenosine and adenosine receptors in the pathogenesis and treatment of rheumatic diseases.

Nat Rev Rheumatol

January 2017

New England Inflammation and Tissue Protection Institute, Northeastern University, 360 Huntington Avenue, 312 MU, Boston, Massachusetts 02115, USA.

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).

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Germinal centers (GCs) are anatomic sites where B cells undergo secondary diversification to produce high-affinity, class-switched Abs. We hypothesized that proliferating B cells in GCs create a hypoxic microenvironment that governs their further differentiation. Using molecular markers, we found GCs to be predominantly hypoxic.

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A2A adenosine receptor antagonists to weaken the hypoxia-HIF-1α driven immunosuppression and improve immunotherapies of cancer.

Curr Opin Pharmacol

August 2016

New England Inflammation and Tissue Protection Institute, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA. Electronic address:

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.

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Proteasomal Inhibition by Ixazomib Induces CHK1 and MYC-Dependent Cell Death in T-cell and Hodgkin Lymphoma.

Cancer Res

June 2016

Division of Hematology Oncology and Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts.

Proteasome-regulated NF-κB has been shown to be important for cell survival in T-cell lymphoma and Hodgkin lymphoma models. Several new small-molecule proteasome inhibitors are under various stages of active preclinical and clinical development. We completed a comprehensive preclinical examination of the efficacy and associated biologic effects of a second-generation proteasome inhibitor, ixazomib, in T-cell lymphoma and Hodgkin lymphoma cells and in vivo SCID mouse models.

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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.

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Immunological mechanisms of the antitumor effects of supplemental oxygenation.

Sci Transl Med

March 2015

New England Inflammation and Tissue Protection Institute, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA. Cancer Vaccine Center, Dana-Farber Cancer Institute, Harvard Institutes of Medicine, 44 Binney Street, Boston, MA 02115, USA.

Antitumor T cells either avoid or are inhibited in hypoxic and extracellular adenosine-rich tumor microenvironments (TMEs) by A2A adenosine receptors. This may limit further advances in cancer immunotherapy. There is a need for readily available and safe treatments that weaken the hypoxia-A2-adenosinergic immunosuppression in the TME.

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Postoperative hyperoxia (60%) worsens hepatic injury in mice.

Anesthesiology

December 2014

From the University Hospital of the Ludwig- Maximilians-University, Department of Anesthesiology, Klinikum Grosshadern, Munich, Germany (Q.Z., A.M., I.K., A.C.); National Institute on Minority Health and Health Disparities, National Institutes of Health, Division of Intramural Research, Bethesda, Maryland (S.H.J.); National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland (A.O., D.L., J.M.W., M.S., A.C.); New England Inflammation and Tissue Protection Institute Consortium at Northeastern University, Boston, Massachusetts (A.O., D.L., M.S.); Mouse Imaging Facility, National Institute of Neurological Disorder and Stroke, National Institutes of Health, Bethesda, Maryland (B.K.); and Department of Anaesthesiology and Intensive Care, Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany (M.T.).

Background: Liver damage by ischemia and reperfusion injury is a risk factor for morbidity and mortality after liver surgery. Postoperative oxygen treatment is routinely applied in the postanesthesia and intensive care unit after liver surgery. The risks of aggravating the injury by increasing inspiratory oxygen from 21 to 60% in the postoperative period were investigated in mice.

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Unlabelled: Intratumoral hypoxia and hypoxia inducible factor-1α (HIF-1-α)-dependent CD39/CD73 ectoenzymes may govern the accumulation of tumor-protecting extracellular adenosine and signaling through A2A adenosine receptors (A2AR) in tumor microenvironments (TME). Here, we explored the conceptually novel motivation to use supplemental oxygen as a treatment to inhibit the hypoxia/HIF-1α-CD39/CD73-driven accumulation of extracellular adenosine in the TME in order to weaken the tumor protection. We report that hyperoxic breathing (60 % O2) decreased the TME hypoxia, as well as levels of HIF-1α and downstream target proteins of HIF-1α in the TME according to proteomic studies in mice.

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Extracellular adenosine-mediated modulation of regulatory T cells.

Front Immunol

July 2014

New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, MA , USA.

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.

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