Adenosine A2A Receptors Intrinsically Regulate CD8+ T Cells in the Tumor Microenvironment

Abstract

Adenosine A 2A receptor (A 2A R) blockade enhances innate and adaptive immune responses. However, mouse genetic studies have shown that A 2A R deletion does not inhibit the growth of all tumor types. In the current study, we showed that growth rates for ectopic melanoma and bladder tumors are increased in Adora2a À/À mice within 2 weeks of tumor inoculation. A 2A R deletion in the host reduced numbers of CD8 þ T cells and effector-memory differentiation of all T cells. To examine intrinsic functions in T cells, we generated mice harboring a T-cell-specific deletion of A 2A R. In this host strain, tumor-bearing mice displayed increased growth of ectopic melanomas, decreased numbers of tumor-associated T cells, reduced effector-memory differentiation, and reduced antiapoptotic IL7Ra (CD127) expression on antigen-experienced cells. Intratumoral pharmacologic blockade similarly reduced CD8 þ T-cell density within tumors in wild-type hosts. We found that A 2A R-proficient CD8 þ T cells specific for melanoma cells displayed a relative survival advantage in tumors. Thus, abrogating A 2A R signaling appeared to reduce IL7R expression, survival, and differentiation of T cells in the tumor microenvironment. One implication of these results is that the antitumor effects of A 2A R blockade that can be mediated by activation of cytotoxic T cells may be overcome in some tumor microenvironments as a result of impaired T-cell maintenance and effector-memory differentiation. Thus, our findings imply that the efficacious application of A 2A R inhibitors for cancer immunotherapy may require careful dose optimization to prevent activation-induced T-cell death in tumors.

Tumor-infiltrating CD39+γδTregs are novel immunosuppressive T cells in human colorectal cancer

“…This inhibitory effect appears to function via CD73 and A2A or A2B receptor. 41,42 This is different from the conventional view that Tregs suppress effector T cells in an IL-10-/or TGF-b-dependent manner. 25,43 Interestingly, a recent study reported that a subset of CRC-infiltrating CD4 C Tregs also express high CD39.…”

Adenosine Receptor 2A Blockade Increases the Efficacy of Anti–PD-1 through Enhanced Antitumor T-cell Responses

“…After 30 minutes digestion at 37 C, cells were twice passed through a 70-mm filter. Single-cell suspensions were then prepared and analyzed by flow cytometry as previously described (14).…”

Methotrexate up-regulates ecto-5′-nucleotidase/CD73 and reduces the frequency of T lymphocytes in the glioblastoma microenvironment

“…For example, ATP and ADP may be hydrolyzed following the overexpression of NTPdase1/CD39 (hereinafter referred to as CD39) in regulatory immune cells, and AMP may be hydrolyzed following the overexpression of ecto-5′-nucleotidase/CD73 (hereinafter referred to as CD73) in cancer cells [5]. Adenosine may in turn modulate the immune cells to form a more suppressive microenvironment in the tumor in a process that is mediated by P1 adenosine receptors (A 1 , A 2A , A 2B , and A 3 ), specifically the A 2A receptor [8].…”