Journal Article

Inhibition of the adenosine A2a receptor modulates expression of T cell coinhibitory receptors and improves effector function for enhanced checkpoint blockade and ACT in murine cancer models

Min-Hee Oh, Im-Hong, Sun, Leone, Robert D, Im-Meng, Sun, Englert, Judson, Wen, Jiayu, Powell, Jonathan D

2018

Overview

Adenosine signaling via the A2a receptor (A2aR) is emerging as an important checkpoint of immune responses. The presence of adenosine in the inflammatory milieu or generated by the CD39/CD73 axis on tissues or T regulatory cells serves to regulate immune responses. By nature of the specialized metabolism of cancer cells, adenosine levels are increased in the tumor microenvironment and contribute to tumor immune evasion. To this end, small molecule inhibitors of the A2aR are being pursued clinically to enhance immunotherapy. Herein, we demonstrate the ability of the novel A2aR antagonist, CPI-444, to dramatically enhance immunologic responses in models of checkpoint therapy and ACT in cancer. Furthermore, we demonstrate that A2aR blockade with CPI-444 decreases expression of multiple checkpoint pathways, including PD-1 and LAG-3, on both CD8+ effector T cells (Teff) and FoxP3+ CD4+ regulatory T cells (Tregs). Interestingly, our studies demonstrate that A2aR blockade likely has its most profound effects during Teff cell activation, significantly decreasing PD-1 and LAG-3 expression at the draining lymph nodes of tumor bearing mice. In contrast to previous reports using A2aR knockout models, pharmacologic blockade with CPI-444 did not impede CD8 T cell persistence or memory recall. Overall these findings not only redefine our understanding of the mechanisms by which adenosine inhibits immunity but also have important implications for the design of novel immunotherapy regimens.

• Publisher: Springer Nature B.V
• Subject: Adenosine / Animal models / Cancer / CD223 antigen / CD4 antigen / CD73 antigen / CD8 antigen / Cell activation / Effector cells / Foxp3 protein / Immune checkpoint / Immune checkpoint inhibitors / Immune response / Immunological memory / Immunoregulation / Immunotherapy / Inflammation / Lymph nodes / Lymphocytes T / Memory cells / PD-1 protein / Receptor mechanisms / T cell receptors / Tumor microenvironment / Tumors