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Cancer Discov. 2019 Dec;9(12):1754-1773. doi: 10.1158/2159-8290.CD-19-0541. Epub 2019 Nov 7.

Targeting CD39 in Cancer Reveals an Extracellular ATP- and Inflammasome-Driven Tumor Immunity.

Author information

1
Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
2
Tizona Therapeutics, San Francisco, California.
3
Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
4
Oncology and Cellular Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
5
Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts.
6
Unit of RNA Biology, Department of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, University of Bonn, Bonn, Germany.
7
Institute of Experimental Oncology (IEO), University Hospital Bonn, University of Bonn, Bonn, Germany.
8
Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
9
Departments of Medicine and Anesthesia, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
10
Medical Genomics Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
11
Translational and Human Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
12
Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. Mark.Smyth@qimrberghofer.edu.au.
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Contributed equally

Abstract

We explored the mechanism of action of CD39 antibodies that inhibit ectoenzyme CD39 conversion of extracellular ATP (eATP) to AMP and thus potentially augment eATP-P2-mediated proinflammatory responses. Using syngeneic and humanized tumor models, we contrast the potency and mechanism of anti-CD39 mAbs with other agents targeting the adenosinergic pathway. We demonstrate the critical importance of an eATP-P2X7-ASC-NALP3-inflammasome-IL18 pathway in the antitumor activity mediated by CD39 enzyme blockade, rather than simply reducing adenosine as mechanism of action. Efficacy of anti-CD39 activity was underpinned by CD39 and P2X7 coexpression on intratumor myeloid subsets, an early signature of macrophage depletion, and active IL18 release that facilitated the significant expansion of intratumor effector T cells. More importantly, anti-CD39 facilitated infiltration into T cell-poor tumors and rescued anti-PD-1 resistance. Anti-human CD39 enhanced human T-cell proliferation and Th1 cytokine production and suppressed human B-cell lymphoma in the context of autologous Epstein-Barr virus-specific T-cell transfer. SIGNIFICANCE: Overall, these data describe a potent and novel mechanism of action of antibodies that block mouse or human CD39, triggering an eATP-P2X7-inflammasome-IL18 axis that reduces intratumor macrophage number, enhances intratumor T-cell effector function, overcomes anti-PD-1 resistance, and potentially enhances the efficacy of adoptive T-cell transfer.This article is highlighted in the In This Issue feature, p. 1631.

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