The nucleoside adenosine accumulates extracellularly in solid tumors and inhibits CD8+ T cells by activating adenosine receptors. The cytokine interleukin-7 (IL-7), which is produced by various tissues and tumors, promotes the survival and maintenance of T cells. Adenosine and IL-7 signaling are being clinically targeted separately or in combination with other therapies for solid tumor indications. Here, we found that IL-7 signaling promoted the accumulation of tumor-associated CD8+ T cells, in part, by preventing adenosine-mediated immunosuppression. Inhibition of the transcription factor FoxO1 downstream of IL-7 receptor signaling was important for protecting CD8+ T cells from suppression by adenosine. These findings have implications for the development of new approaches for cancer immunotherapies that target the adenosine pathway.

Ecto-5′-nucleotidase (CD73) is an enzyme present on the surface of tumor cells whose primary described function is the production of extracellular adenosine. Due to the immunosuppressive properties of adenosine, CD73 is being investigated as a target for new antitumor therapies. We and others have described that CD73 is present at the surface of different CD8+ T cell subsets. Nonetheless, there is limited information as to whether CD73 affects CD8+ T cell proliferation and survival. In this study, we assessed the impact of CD73 deficiency on CD8+ T cells by analyzing their proliferation and survival in antigenic and homeostatic conditions. Results obtained from adoptive transfer experiments demonstrate a paradoxical role of CD73. On one side, it favors the expression of interleukin-7 receptor α chain on CD8+ T cells and their homeostatic survival; on the other side, it reduces the survival of activated CD8+ T cells under antigenic stimulation. Also, upon in vitro antigenic stimulation, CD73 decreases the expression of interleukin-2 receptor α chain and the anti-apoptotic molecule Bcl-2, findings that may explain the reduced CD8+ T cell survival observed in this condition. These results indicate that CD73 has a dual effect on CD8+ T cells depending on whether they are subject to an antigenic or homeostatic stimulus, and thus, special attention should be given to these aspects when considering CD73 blockade in the design of novel antitumor therapies.