Data from Autocrine Adenosine Regulates Tumor Polyfunctional CD73<sup>+</sup>CD4<sup>+</sup> Effector T Cells Devoid of Immune Checkpoints

Abstract

<div>Abstract<p>The production of CD73-derived adenosine (Ado) by Tregs has been proposed as a resistance mechanism to anti-PD-1 therapy in murine tumor models. We reported that human Tregs express the ectonucleotidase CD39, which generates AMP from ATP, but do not express the AMPase CD73. In contrast, CD73 defined a subset of effector CD4<sup>+</sup> T cells (Teffs) enriched in polyfunctional Th1.17 cells characterized by expression of CXCR3, CCR6, and MDR1, and production of IL17A/IFNγ/IL22/GM-CSF. CD39<sup>+</sup> Tregs selectively targeted CD73<sup>+</sup> Teffs through cooperative degradation of ATP into Ado inhibiting and restricting the ability of CD73<sup>+</sup> Teffs to secrete IL17A. CD73<sup>+</sup> Teffs infiltrating breast and ovarian tumors were functionally blunted by Tregs expressing upregulated levels of CD39 and ATPase activity. Moreover, tumor-infiltrating CD73<sup>+</sup> Teffs failed to express inhibitory immune checkpoints, suggesting that CD73 might be selected under pressure from immune checkpoint blockade therapy and thus may represent a nonredundant target for restoring antitumor immunity.</p><p><b>Significance:</b> Polyfunctional CD73<sup>+</sup> T-cell effectors lacking other immune checkpoints are selectively targeted by CD39 overexpressing Tregs that dominate the breast tumor environment. <i>Cancer Res; 78(13); 3604–18. ©2018 AACR</i>.</p></div>