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Nat Immunol. 2019 Jan 21;20(3):265-275. doi: 10.1038/s41590-018-0292-y.

Metabolic rewiring of macrophages by CpG potentiates clearance of cancer cells and overcomes tumor-expressed CD47-mediated 'don't-eat-me' signal.

Author information

1
Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
2
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
3
AJ Drexel Autism Institute, Drexel University, Philadelphia, PA, USA.
4
Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA.
5
Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. gregory.beatty@uphs.upenn.edu.
6
Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. gregory.beatty@uphs.upenn.edu.

Abstract

Macrophages enforce antitumor immunity by engulfing and killing tumor cells. Although these functions are determined by a balance of stimulatory and inhibitory signals, the role of macrophage metabolism is unknown. Here, we study the capacity of macrophages to circumvent inhibitory activity mediated by CD47 on cancer cells. We show that stimulation with a CpG oligodeoxynucleotide, a Toll-like receptor 9 agonist, evokes changes in the central carbon metabolism of macrophages that enable antitumor activity, including engulfment of CD47+ cancer cells. CpG activation engenders a metabolic state that requires fatty acid oxidation and shunting of tricarboxylic acid cycle intermediates for de novo lipid biosynthesis. This integration of metabolic inputs is underpinned by carnitine palmitoyltransferase 1A and adenosine tri-phosphate citrate lyase, which, together, impart macrophages with antitumor potential capable of overcoming inhibitory CD47 on cancer cells. Our findings identify central carbon metabolism to be a novel determinant and potential therapeutic target for stimulating antitumor activity by macrophages.

PMID:
30664738
PMCID:
PMC6380920
[Available on 2019-07-21]
DOI:
10.1038/s41590-018-0292-y
[Indexed for MEDLINE]

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