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

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1 juillet 2018

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Serveur académique Lausannois

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Ce document est lié à :
info:eu-repo/semantics/altIdentifier/doi/10.1158/0008-5472.CAN-17-2405

Ce document est lié à :
info:eu-repo/semantics/altIdentifier/pmid/29559470

Ce document est lié à :
info:eu-repo/semantics/altIdentifier/eissn/1538-7445

Ce document est lié à :
info:eu-repo/semantics/altIdentifier/urn/urn:nbn:ch:serval-BIB_028E2FB272C50

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Serveur Académique Lausannois

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Université de Lausanne et CHUV

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info:eu-repo/semantics/openAccess , All rights reserved , https://serval.unil.ch/disclaimer

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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

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Breasts

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N. Gourdin et al., « Autocrine Adenosine Regulates Tumor Polyfunctional CD73+CD4+ Effector T Cells Devoid of Immune Checkpoints. », Serveur académique Lausannois, ID : 10.1158/0008-5472.CAN-17-2405

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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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