Autocrine Adenosine regulates tumor polyfunctional CD73+CD4+ effector T cells devoid of immune checkpoints

Abstract : 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+ 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+ Tregs selectively targeted CD73+ Teffs through cooperative degradation of ATP into Ado inhibiting and restricting the ability of CD73+ Teffs to secrete IL17A. CD73+ Teffs infiltrating breast and ovarian tumors were functionally blunted by Tregs expressing upregulated levels of CD39 and ATPase activity. Moreover, tumor-infiltrating CD73+ 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.Significance: Polyfunctional CD73+ T-cell effectors lacking other immune checkpoints are selectively targeted by CD39 overexpressing Tregs that dominate the breast tumor environment. Cancer Res; 78(13); 3604-18. ©2018 AACR.
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Soumis le : vendredi 13 septembre 2019 - 11:49:38
Dernière modification le : mardi 17 septembre 2019 - 11:17:57

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Nicolas Gourdin, Marion Bossennec, Céline Rodriguez, Selena Vigano, Christelle Machon, et al.. Autocrine Adenosine regulates tumor polyfunctional CD73+CD4+ effector T cells devoid of immune checkpoints. Cancer Research, American Association for Cancer Research, 2018, 78 (13), pp.3604-3618. ⟨10.1158/0008-5472.CAN-17-2405⟩. ⟨hal-02285966⟩

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