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

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Version: Author's accepted manuscript
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Serval ID
serval:BIB_028E2FB272C5
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Autocrine Adenosine Regulates Tumor Polyfunctional CD73<sup>+</sup>CD4<sup>+</sup> Effector T Cells Devoid of Immune Checkpoints.
Journal
Cancer research
Author(s)
Gourdin N., Bossennec M., Rodriguez C., Vigano S., Machon C., Jandus C., Bauché D., Faget J., Durand I., Chopin N., Tredan O., Marie J.C., Dubois B., Guitton J., Romero P., Caux C., Ménétrier-Caux C.
ISSN
1538-7445 (Electronic)
ISSN-L
0008-5472
Publication state
Published
Issued date
01/07/2018
Peer-reviewed
Oui
Volume
78
Number
13
Pages
3604-3618
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
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 <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.Significance: Polyfunctional CD73 <sup>+</sup> 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.
Keywords
5'-Nucleotidase/metabolism, Adenosine/metabolism, Antineoplastic Agents, Immunological/pharmacology, Antineoplastic Agents, Immunological/therapeutic use, Apyrase/metabolism, Breast Neoplasms/drug therapy, Breast Neoplasms/immunology, Breast Neoplasms/pathology, Costimulatory and Inhibitory T-Cell Receptors/antagonists & inhibitors, Costimulatory and Inhibitory T-Cell Receptors/metabolism, Drug Resistance, Neoplasm/immunology, Female, GPI-Linked Proteins/metabolism, Humans, Interleukin-17/metabolism, Lymphocytes, Tumor-Infiltrating/immunology, Lymphocytes, Tumor-Infiltrating/metabolism, Ovarian Neoplasms/drug therapy, Ovarian Neoplasms/immunology, Ovarian Neoplasms/pathology, T-Lymphocytes, Helper-Inducer/immunology, T-Lymphocytes, Helper-Inducer/metabolism, T-Lymphocytes, Regulatory/immunology, T-Lymphocytes, Regulatory/metabolism, Tumor Escape/immunology
Pubmed
Web of science
Open Access
Yes
Create date
26/04/2018 15:13
Last modification date
04/05/2021 6:36
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