Adenosine signaling promotes double-negative T-cell anticancer responses in conditions of CD8 T-cell lymphopenia

• Identification of a druggable pathway for generating antitumor double-negative T-cells under conditions of CD8+ T-cell lymphopenia • Evaluation of the antileukemic drug forodesine for generating antitumor double-negative T-cells under conditions of CD8+ T-cell lymphopenia CD8 T-cell lymphopenia is observed in a variety of conditions and has been linked with poorer survival and increased risk of developing cancer and infections. Increase in Double-Negative T-cells (DNTs), a subset of T-cells which lack CD8 and CD4 co-receptors, has been reported in both human patients with CD8 T-cell lymphopenia and in mice depleted of CD8 T-cells. Promoting the generation of immunoprotective DNTs could compensate for the lack of CD8 T-cells in affected patients, but strategies to generate protective DNTs remain unclear. In this study, we found that it is possible to promote immunoprotective antitumor DNT cells under conditions of CD8 T-cells lymphopenia using the antileukemic drug forodesine (Foro). This work could have significant therapeutic implications for patients with CD8 T-cells lymphopenia, including patients with cancer.