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Cancer Discov. 2019 Dec 7.

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

Li XY, Moesta AK, Xiao C, Nakamura K, Casey M, Zhang H, Madore J, Lepletier A, Roman Aguilera A, Sundarrajan A, Jacoberger-Foissac C, Wong C, Dela Cruz T, Welch M, Lerner AG, Spatola BN, Soros VB, Corbin J, Anderson AC, Effern M, Holzel M, Robson SC, Johnston RL, Waddell N, Smith C, Bald T, Geetha N, Beers C, Teng MWL, Smyth MJ

We explored the mechanism of action of CD39 antibodies that inhibit ecto-enzyme CD39 conversion of extracellular ATP (eATP) to AMP and thus potentially augment eATP-P2-mediated pro-inflammatory responses. Using syngeneic and humanized tumor models, we contrast the potency and mechanism of anti-CD39 mAbs compared with other agents targeting the adenosinergic pathway. We demonstrate the critical importance of an eATP-P2X7-ASC-NALP3-inflammasome-IL-18 pathway in the anti-tumor 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 co-expression on intratumor myeloid subsets, an early signature of macrophage depletion, and active IL-18 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-PD1 resistance. Anti-human CD39 enhanced human T-cell proliferation and Th1 cytokine production and suppressed human B cell lymphoma in the context of autologous EBV-specific T cell transfer.

PMID: 31699796