Mechanisms Driving Neutrophil-Induced T-cell Immunoparalysis in Ovarian Cancer.
Journal
Cancer immunology research
ISSN: 2326-6074
Titre abrégé: Cancer Immunol Res
Pays: United States
ID NLM: 101614637
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
received:
05
11
2020
revised:
05
02
2021
accepted:
12
05
2021
pubmed:
16
5
2021
medline:
22
2
2022
entrez:
15
5
2021
Statut:
ppublish
Résumé
T-cell activation and expansion in the tumor microenvironment (TME) are critical for antitumor immunity. Neutrophils in the TME acquire a complement-dependent T-cell suppressor phenotype that is characterized by inhibition of T-cell proliferation and activation through mechanisms distinct from those of myeloid-derived suppressor cells. In this study, we used ascites fluid supernatants (ASC) from patients with ovarian cancer as an authentic component of the TME to evaluate the effects of ASC on neutrophil function and mechanisms for neutrophil-driven immune suppression. ASC prolonged neutrophil life span, decreased neutrophil density, and induced nuclear hypersegmentation. Mass cytometry analysis showed that ASC induced 15 distinct neutrophil clusters. ASC stimulated complement deposition and signaling in neutrophils, resulting in surface mobilization of granule constituents, including NADPH oxidase. NADPH oxidase activation and phosphatidylserine signaling were required for neutrophil suppressor function, although we did not observe a direct role of extracellular reactive oxygen species in inhibiting T-cell proliferation. Postoperative surgical drainage fluid also induced a complement-dependent neutrophil suppressor phenotype, pointing to this effect as a general response to injury. Like circulating lymphocytes, ASC-activated neutrophils caused complement-dependent suppression of tumor-associated lymphocytes. ASC-activated neutrophils adhered to T cells and caused trogocytosis of T-cell membranes. These injury and signaling cues resulted in T-cell immunoparalysis characterized by impaired NFAT translocation, IL2 production, glucose uptake, mitochondrial function, and mTOR activation. Our results demonstrate that complement-dependent priming of neutrophil effector functions in the TME induces a T-cell nonresponsiveness distinct from established checkpoint pathways and identify targets for immunotherapy.
Identifiants
pubmed: 33990375
pii: 2326-6066.CIR-20-0922
doi: 10.1158/2326-6066.CIR-20-0922
pmc: PMC8287091
mid: NIHMS1706683
doi:
Types de publication
Journal Article
Observational Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
790-810Subventions
Organisme : NCI NIH HHS
ID : P30 CA016056
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI119965
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA188900
Pays : United States
Organisme : NIAID NIH HHS
ID : U01 AI138318
Pays : United States
Organisme : NIH HHS
ID : S10 OD018048
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
©2021 American Association for Cancer Research.
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