Adenosine signaling promotes double-negative T-cell anticancer responses in 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. An increase in double-negative T cells (DNTs), a subset of T cells that lack CD8 and CD4 coreceptors, has been reported in both human patients with CD8 T-cell lymphopenia and 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 DNTs under conditions of CD8 T-cell lymphopenia using the antileukemic drug forodesine. This work could have significant therapeutic implications for patients with CD8 T-cell lymphopenia, including patients with cancer.