Targeting CD39 in Cancer Reveals an Extracellular ATP- and Inflammasome-Driven Tumor Immunity
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Dec 01, 2019
- Source ID
- 10.1158/2159-8290.cd-19-0541
Entities
People
- Achim Moesta
- Ailin Lepletier
- Alana G. Lerner
- Amelia Roman Aguilera
- Ana C. Anderson
- Ashmitha Sundarrajan
- Bradley N. Spatola
- Celia Jacoberger-foissac
- Christos Xiao
- Clifford Wong
- Corey Smith
- Courtney Beers
- Haiyan Zhang
- Jason Madore
- John Corbin
- Kyohei Nakamura
- Maike Effern
- Mark J. Smyth
- Megan Welch
- Michael Hölzel
- Michele W.L. Teng
- Mika Casey
- Nicola Waddell
- Nishamol Geetha
- Rebecca L. Johnston
- Simon C. Robson
- Tobias Bald
- Tracy Dela Cruz
- Vanessa B. Soros
- Xian-Yang Li
Organizations
- Beth Israel Deaconess Medical Center
- Brigham and Women's Hospital
- National Health and Medical Research Council
- QIMR Berghofer Medical Research Institute
- University of Bonn
- University of Melbourne