β2-adrenergic receptor signaling regulates metabolic pathways critical to myeloid-derived suppressor cell function within the TME

Myeloid-derived suppressor cells (MDSCs) impede antitumor immunity; however, the precise mechanisms that regulate their suppressive function remain unresolved. Identifying these mechanisms could lead to therapeutic interventions to boost cancer immunotherapy efficacy. Here, we reveal that β2 adrener...

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Vydané v:	Cell reports (Cambridge) Ročník 37; číslo 4; s. 109883
Hlavní autori:	Mohammadpour, Hemn, MacDonald, Cameron R., McCarthy, Philip L., Abrams, Scott I., Repasky, Elizabeth A.
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States Elsevier Inc 26.10.2021
Predmet:	Animals autophagy cancer fatty acid oxidation immune suppression Lipid Metabolism - genetics Lipid Metabolism - immunology MDSCs metabolism Mice Mice, Knockout Myeloid-Derived Suppressor Cells - metabolism Neoplasm Proteins - genetics Neoplasm Proteins - immunology Neoplasms - genetics Neoplasms - immunology Oxidative Phosphorylation prostaglandin E2 Receptors, Adrenergic, beta-2 - genetics Receptors, Adrenergic, beta-2 - immunology Signal Transduction - immunology stress Tumor Microenvironment - genetics Tumor Microenvironment - immunology β-adrenergic signaling stress MDSCs autophagy prostaglandin E2 cancer metabolism β-adrenergic signaling fatty acid oxidation immune suppression oxidative phosphorylation
ISSN:	2211-1247, 2211-1247
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Shrnutí:	Myeloid-derived suppressor cells (MDSCs) impede antitumor immunity; however, the precise mechanisms that regulate their suppressive function remain unresolved. Identifying these mechanisms could lead to therapeutic interventions to boost cancer immunotherapy efficacy. Here, we reveal that β2 adrenergic receptor (β2-AR) expression on MDSCs increases with tumor growth and that the β2-AR stress pathway drives the immune suppressive activity of MDSCs by altering their metabolism. We show that β2-AR signaling decreases glycolysis and increases oxidative phosphorylation and fatty acid oxidation (FAO). It also increases expression of the fatty acid transporter CPT1A, which is necessary for the FAO-mediated immunosuppressive function of MDSCs. Moreover, we show that β2-AR signaling increases autophagy and activates the arachidonic acid cycle, both required for increasing the release of the immunosuppressive mediator, PGE2. Our data reveal that β2-AR signaling triggered by stress is an important physiological regulator of key metabolic pathways in MDSCs, driving their immunosuppressive function. [Display omitted] •Tumor progression increases the expression of β2-AR on MDSCs•β2-AR signaling increases fatty acid oxidation and oxidative phosphorylation in MDSCs•β2-AR signaling in MDSCs increases autophagy-mediated PGE2 production Mohammadpour et al. show that β2-AR signaling in MDSCs alters their metabolic state and increases their immunosuppressive function. Specific processes found to be increased include fatty acid oxidation, oxidative phosphorylation, and autophagy. In addition, these metabolic alterations facilitate an increase in PGE2 production via elevated COX2 expression.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 H.M. initiated and H.M., C.R.M., S.I.A., and E.A.R. designed the study; H.M. performed the experiments, with assistance from C.R.M. H.M., C.R.M., P.L.M., S.I.A., and E.A.R. analyzed and interpreted the data and wrote the paper. AUTHOR CONTRIBUTIONS
ISSN:	2211-1247 2211-1247
DOI:	10.1016/j.celrep.2021.109883