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 proinfl ammatory 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-NALP3infl ammasome-IL18 pathway in the antitumor activity mediated by CD39 enzyme blockade, rather than simply reducing adenosine as mechanism of action. Effi cacy 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 signifi cant expansion of intratumor effector T cells. More importantly, anti-CD39 facilitated infi ltration 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-specifi c 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-infl ammasome-IL18 axis that reduces intratumor macrophage number, enhances intratumor T-cell effector function, overcomes anti-PD-1 resistance, and potentially enhances the effi cacy of adoptive T-cell transfer.

P2X7 in Cancer: From Molecular Mechanisms to Therapeutics

“…In the TME, the permanent release of DAMPs including ATP, high mobility group box 1 (HMGB1) and calreticulin (CRT) drives chronic inflammatory settings that are supplemented by immunosuppressive signals leading to a dampening of immune effector cell responses (Galluzzi et al, 2017). By responding to ATP proinflammatory signals, P2X7 counterbalances the potent immunosuppressive signaling driven by the ATP degradation product, adenosine (Li et al, 2019). In the following section, we describe the role of P2X7 in inflammation and immunity and use this as a foundation to define the role of P2X7 in the TME.…”

The yin and yang functions of extracellular ATP and adenosine in tumor immunity

“…They participate in tumor genesis and development through various mechanisms. In TME, eATP boosts antitumor immune responses while ADO attenuates immune response against tumors [10,11]. eATP and ADO, like yin and yang, represent two opposite aspects from immune-activating to immune-suppressive signals in tumor immunity.…”

Role of inflammasome activation in tumor immunity triggered by immune checkpoint blockers

“…More recently, Li et al . have shown in MC38 tumors that anti‐CD39 is less effective in Casp1/11 −/− , Nlrp3 −/− , Pycard −/− and P2x7r −/− mice [54]. Using syngeneic and humanized tumor models, the authors also showed that CD39 and PD‐1 blockade have synergistic anti‐tumoral effects [54].…”

“…In spite of considerable progress showing that CD8 + T cells mediate anti‐tumor immune responses when inflammasome is unleashed [48,54], the mechanisms by which inflammasomes promote anti‐tumor immunity in the context of ICBs remain unclear. Inflammasomes may regulate priming of cytotoxic T lymphocytes.…”

“…Thus, TMEM176B and CD39 may serve as two different physiological strategies to impair ATP‐induced inflammation mediated by inflammasomes and Th17 cells. Pharmacological blockade of TMEM176B and CD39 led to inflammasome‐dependent tumor immunity and enhanced anti‐tumor efficacy of ICBs [48,54]. Thus, concomitant blockade of both TMEM176B and CD39 may trigger Th17‐dependent responses and enhance the efficacy of ICBs.…”