PARP-inhibition reprograms macrophages toward an anti-tumor phenotype.
CP: Cancer
NAD+
PARP-inhibitor
macrophages
tumor immunology
tumor metabolism
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
11 10 2022
11 10 2022
Historique:
received:
15
11
2021
revised:
14
07
2022
accepted:
16
09
2022
entrez:
12
10
2022
pubmed:
13
10
2022
medline:
15
10
2022
Statut:
ppublish
Résumé
Poly(ADP)ribosylation inhibitors (PARPis) are toxic to cancer cells with homologous recombination (HR) deficiency but not to HR-proficient cells in the tumor microenvironment (TME), including tumor-associated macrophages (TAMs). As TAMs can promote or inhibit tumor growth, we set out to examine the effects of PARP inhibition on TAMs in BRCA1-related breast cancer (BC). The PARPi olaparib causes reprogramming of TAMs toward higher cytotoxicity and phagocytosis. A PARPi-related surge in NAD+ increases glycolysis, blunts oxidative phosphorylation, and induces reverse mitochondrial electron transport (RET) with an increase in reactive oxygen species (ROS) and transcriptional reprogramming. This reprogramming occurs in the absence or presence of PARP1 or PARP2 and is partially recapitulated by addition of NAD derivative methyl-nicotinamide (MNA). In vivo and ex vivo, the effect of olaparib on TAMs contributes to the anti-tumor efficacy of the PARPi. In vivo blockade of the "don't-eat-me signal" with CD47 antibodies in combination with olaparib improves outcomes in a BRCA1-related BC model.
Identifiants
pubmed: 36223740
pii: S2211-1247(22)01307-9
doi: 10.1016/j.celrep.2022.111462
pmc: PMC9727835
mid: NIHMS1842064
pii:
doi:
Substances chimiques
CD47 Antigen
0
Phthalazines
0
Poly(ADP-ribose) Polymerase Inhibitors
0
Reactive Oxygen Species
0
NAD
0U46U6E8UK
Niacinamide
25X51I8RD4
Adenosine Diphosphate
61D2G4IYVH
Banques de données
ClinicalTrials.gov
['NCT02624973']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
111462Subventions
Organisme : NIBIB NIH HHS
ID : T32 EB025823
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA226776
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA197459
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA120964
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA168504
Pays : United States
Informations de copyright
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests N.Y.R.A. is key opinion leader for Bruker Daltonics, scientific advisor to Invicro, and receives support from Thermo Finnegan and EMD Serono. H.P.E. reports personal fees (honoraria, consulting, or advisory role) from Amgen, AstraZeneca, Abbvie, Bristol-Myers-Squibb, Daiichi Sankyo, Dagens Medisin, Eli Lilly, HAI Interaktiv AS, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi, and Seagen. G.M.W. reports grants from Merck & Co. and institutional support from Glaxo Smith Kline outside the submitted work. In addition, G.M.W. has US patent 20090258352 A1 Pin1 as a marker for abnormal cell growth licensed to Cell Signaling, R&D Systems. O.S. is a 2seventy bio employee and obtains compensation and has equity in the company. H.P.E. received institutional funding from AstraZeneca (ESR-14-10077) and Pfizer (GMGS 51752519).
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