Cotargeting CD73 and A2AR overcomes host-ablated A2AR–induced CD73 expression.

  • Major finding: Cotargeting CD73 and A2AR overcomes host-ablated A2AR–induced CD73 expression.

  • Mechanism: Fc receptor engagement of anti-CD73 augments antimetastatic activity and promotes cytokine release.

  • Impact: Targeting multiple adenosinergic signaling components may be a cancer immunotherapeutic strategy.

The ectoenzyme CD73 generates adenosine, which binds to the adenosine A2A receptor (A2AR, encoded by ADORA2A) to activate downstream effectors that repress the antitumor immune response in the tumor microenvironment (TME). Targeting the adenosinergic pathway enhances the efficacy of immune checkpoint blockade, suggesting that the combination of inhibitors of adenosine signaling with immunomodulatory therapies may improve patient outcomes. To assess the impact of targeting adenosine signaling at critical nodal points on tumorigenesis, Young and colleagues generated transgenic mice depleted of CD73 and A2AR (DKO mice). DKO mice exhibited decreased tumor burden and metastasis compared to wild-type (WT) mice, and displayed decreased tumor initiation compared to A2AR KO mice and CD73 KO mice, suggesting that CD73 and A2AR are not functionally redundant. Intratumoral levels of tumor-infiltrating leukocytes, particularly CD8+ T cells, were increased in tumor-bearing A2AR KO and DKO mice, but not in tumor-bearing CD73 KO mice, compared to tumor-bearing WT mice. A2AR KO mice exhibited increased CD73 expression in the tumor core and on host endothelium and tumor. However, DKO mice were unable to increase CD73 expression within the TME, suggesting that the loss of A2AR, which induces CD73 expression in first the host, then the tumor, is a possible tumor escape mechanism. Combined treatment of murine metastatic tumor models with a small-molecule inhibitor of A2AR and an anti-CD73 antibody resulted in greater antimetastatic efficacy than monotherapy treatment, and maximal therapeutic efficacy of the combination treatment was dependent on Fc receptor (FcR) engagement of anti-CD73. Further, anti-CD73 monotherapy induced the expansion of CD11b+Gr1hi neutrophils, which were required for anti-CD73–mediated efficacy, and in a human in vitro system, FcR engagement of anti-CD73 resulted in increased cytokine release. Collectively, these findings show that coinhibition of A2AR and CD73 is necessary for maximal antitumor efficacy, identify a potential mechanism underlying optimal anti-CD73 therapy, and describe the distinct immunomodulatory role of CD73 in the TME.

Young A, Ngiow SF, Barkauskas DS, Sult E, Hay C, Blake SJ, et al. Co-inhibition of CD73 and A2AR adenosine signaling improves anti-tumor immune responses. Cancer Cell 2016;30:391–403.