A2AR Adenosine Signaling Suppresses Natural Killer Cell Maturation in the Tumor Microenvironment

Abstract

Extracellular adenosine is a key immunosuppressive metabolite that restricts activation of cytotoxic lymphocytes and impairs antitumor immune responses. Here, we show that engagement of A2A adenosine receptor (A2AR) acts as a checkpoint that limits the maturation of natural killer (NK) cells. Both global and NK-cell-specific conditional deletion of A2AR enhanced proportions of terminally mature NK cells at homeostasis, following reconstitution, and in the tumor microenvironment. Notably, A2AR-deficient, terminally mature NK cells retained proliferative capacity and exhibited heightened reconstitution in competitive transfer assays. Moreover, targeting A2AR specifically on NK cells also improved tumor control and delayed tumor initiation. Taken together, our results establish A2AR-mediated adenosine signaling as an intrinsic negative regulator of NK-cell maturation and antitumor immune responses. On the basis of these findings, we propose that administering A2AR antagonists concurrently with NK cell-based therapies may heighten therapeutic benefits by augmenting NK cell-mediated antitumor immunity. Ablating adenosine signaling is found to promote natural killer cell maturation and antitumor immunity and reduce tumor growth. .

The role of NK cells and CD39 in the immunological control of tumor metastases

“…In our previous work, we illustrated in naïve mice that the most terminally differentiated NK cells express CD39, but many NK cells did not express CD39. 30 Further assessment of CD39 + and CD39 − NK cells will be required to determine any distinctions in their function. Like many other immunosuppressive pathways, such as PD-L1, 31 the major site of action of CD39 may be very model and disease context dependent.…”

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

“…Adenosine signaling in the TME can reduce NK cell proliferation and activation, as well as its effector function (327)(328)(329). Blocking adenosine-catalyzing enzymes and purinergic signaling in the TME (such as antibodies against CD73, CD39, and CD38, which mediate the production of extracellular adenosine, and blockade of A 2A R) is therefore being investigated in multiple clinical trials in combination with immune checkpoint blockade (330) and may synergistically enhance tumor-resident NK cell activity (330)(331)(332)(333)(334)(335)(336)(337)(338).…”

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

“…A2AR activation on natural killer (NK) cells inhibits NK cell maturation, proliferation, activation, production of cytotoxic cytokines (e.g., IFN-γ and TNF-α), and target cell killing (38,(101)(102)(103)(104)(105)(106)(107). Whereas, genetic deletion or pharmacological FIGURE 1 | Extracellular adenosine synthesis, adenosine receptor signaling, and adenosine-mediated immunosuppression.…”

“…Frontiers in Immunology | www.frontiersin.org blockade of A2AR or respiratory hyperoxia restores NK cell maturation, proliferative capacity, and cytotoxic function, which improves control over tumor growth, delays tumor initiation and suppresses tumor metastasis (38,101,102). CD73 and/or A2AR blockade or supplemental oxygen in combination with therapies promoting NK cell activity may be relevant strategies to enhance antitumor immunity.…”