Diacylglycerol kinase ζ limits IL-2-dependent control of PD-1 expression in tumor-infiltrating T lymphocytes.
CD8-positive T-lymphocytes
drug evaluation
immune evation
immunotherapy
preclinical
programmed cell death 1 receptor
Journal
Journal for immunotherapy of cancer
ISSN: 2051-1426
Titre abrégé: J Immunother Cancer
Pays: England
ID NLM: 101620585
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
accepted:
05
11
2020
entrez:
28
11
2020
pubmed:
29
11
2020
medline:
18
9
2021
Statut:
ppublish
Résumé
The inhibitory functions triggered by the programmed cell death-1 (PD-1) receptor following binding to its ligand (PD-L1) protect healthy organs from cytotoxic T cells, and neutralize antitumor T cell attack. Antibody-based therapies to block PD-1/PD-L1 interaction have yielded notable results, but most patients eventually develop resistance. This failure is attributed to CD8 We used a human triple parameter reporter cell line to examine the consequences of DGKζ depletion on the transcriptional restriction imposed by PD-1 ligation. We studied the effect of DGKζ deficiency on PD-1 expression dynamics, as well as the impact of DGKζ absence on the in vivo growth of MC38 adenocarcinoma cells. We demonstrate that DGKζ depletion enhances DAG-regulated transcriptional programs, promoting interleukin-2 production and partially counteracting PD-1 inhibitory functions. DGKζ loss results in limited PD-1 expression and enhanced expansion of cytotoxic CD8 Our results, which define a role for DGKζ in the control of PD-1 expression, confirm DGKζ potential as a therapeutic target as well as a biomarker of CD8
Sections du résumé
BACKGROUND
The inhibitory functions triggered by the programmed cell death-1 (PD-1) receptor following binding to its ligand (PD-L1) protect healthy organs from cytotoxic T cells, and neutralize antitumor T cell attack. Antibody-based therapies to block PD-1/PD-L1 interaction have yielded notable results, but most patients eventually develop resistance. This failure is attributed to CD8
METHODS
We used a human triple parameter reporter cell line to examine the consequences of DGKζ depletion on the transcriptional restriction imposed by PD-1 ligation. We studied the effect of DGKζ deficiency on PD-1 expression dynamics, as well as the impact of DGKζ absence on the in vivo growth of MC38 adenocarcinoma cells.
RESULTS
We demonstrate that DGKζ depletion enhances DAG-regulated transcriptional programs, promoting interleukin-2 production and partially counteracting PD-1 inhibitory functions. DGKζ loss results in limited PD-1 expression and enhanced expansion of cytotoxic CD8
CONCLUSIONS
Our results, which define a role for DGKζ in the control of PD-1 expression, confirm DGKζ potential as a therapeutic target as well as a biomarker of CD8
Identifiants
pubmed: 33246984
pii: jitc-2020-001521
doi: 10.1136/jitc-2020-001521
pmc: PMC7703416
pii:
doi:
Substances chimiques
IL2 protein, human
0
Interleukin-2
0
PDCD1 protein, human
0
Pdcd1 protein, mouse
0
Programmed Cell Death 1 Receptor
0
Diacylglycerol Kinase
EC 2.7.1.107
diacylglycerol kinase zeta, mouse
EC 2.7.1.107
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: None declared.
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