Targeting CD39 in cancer reveals an extracellular ATP-and inflammasome-driven tumor immunity

Xian Yang Li, Achim K. Moesta, Christos Xiao, Kyohei Nakamura, Mika Casey, Haiyan Zhang, Jason Madore, Ailin Lepletier, Amelia Roman Aguilera, Ashmitha Sundarrajan, Celia Jacoberger-Foissac, Clifford Wong, Tracy de la Cruz, Megan Welch, Alana G. Lerner, Bradley N. Spatola, Vanessa B. Soros, John Corbin, Ana C. Anderson, Maike EffernMichael Hölzel, Simon C. Robson, Rebecca L. Johnston, Nicola Waddell, Corey Smith, Tobias Bald, Nishamol Geetha, Courtney Beers, Michele W.L. Teng, Mark J. Smyth

Research output: Contribution to journalArticle

Abstract

We explored the mechanism of action of CD39 antibodies that inhibit ectoen-zyme 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.

Original languageEnglish
Pages (from-to)1754-1773
Number of pages20
JournalCancer Discovery
Volume9
Issue number12
DOIs
Publication statusPublished - Dec 2019

ASJC Scopus subject areas

  • Oncology

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    Li, X. Y., Moesta, A. K., Xiao, C., Nakamura, K., Casey, M., Zhang, H., Madore, J., Lepletier, A., Aguilera, A. R., Sundarrajan, A., Jacoberger-Foissac, C., Wong, C., de la Cruz, T., Welch, M., Lerner, A. G., Spatola, B. N., Soros, V. B., Corbin, J., Anderson, A. C., ... Smyth, M. J. (2019). Targeting CD39 in cancer reveals an extracellular ATP-and inflammasome-driven tumor immunity. Cancer Discovery, 9(12), 1754-1773. https://doi.org/10.1158/2159-8290.CD-19-0541