Myeloid-derived suppressor cell mitochondrial fitness governs chemotherapeutic efficacy in hematologic malignancies

Myeloid derived suppressor cells (MDSCs) are key regulators of immune responses and correlate with poor outcomes in hematologic malignancies. Here, we identify that MDSC mitochondrial fitness controls the efficacy of doxorubicin chemotherapy in a preclinical lymphoma model. Mechanistically, we show...

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Vydané v:Nature communications Ročník 15; číslo 1; s. 2803 - 19
Hlavní autori: Daneshmandi, Saeed, Choi, Jee Eun, Yan, Qi, MacDonald, Cameron R., Pandey, Manu, Goruganthu, Mounika, Roberts, Nathan, Singh, Prashant K., Higashi, Richard M., Lane, Andrew N., Fan, Teresa W-M., Wang, Jianmin, McCarthy, Philip L., Repasky, Elizabeth A., Mohammadpour, Hemn
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: London Nature Publishing Group UK 30.03.2024
Nature Publishing Group
Nature Portfolio
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13/2
13/31
13/95
631/250/1932
631/45/320
631/67/2327
Adrenergic receptors
Blood cancer
Chemotherapy
Disruption
Down-regulation
Doxorubicin
Effectiveness
Electron transport
Electron transport chain
Energy metabolism
Fitness
Glutamine
Humanities and Social Sciences
Immune response
Lymphoma
Malignancy
Metabolism
Mitochondria
multidisciplinary
Oxidative stress
Reactive oxygen species
Receptor mechanisms
Receptors (physiology)
Science
Science (multidisciplinary)
Stat3 protein
Suppressor cells
Tricarboxylic acid cycle
Tumorigenesis
ISSN:2041-1723, 2041-1723
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Shrnutí:Myeloid derived suppressor cells (MDSCs) are key regulators of immune responses and correlate with poor outcomes in hematologic malignancies. Here, we identify that MDSC mitochondrial fitness controls the efficacy of doxorubicin chemotherapy in a preclinical lymphoma model. Mechanistically, we show that triggering STAT3 signaling via β2-adrenergic receptor (β2-AR) activation leads to improved MDSC function through metabolic reprograming, marked by sustained mitochondrial respiration and higher ATP generation which reduces AMPK signaling, altering energy metabolism. Furthermore, induced STAT3 signaling in MDSCs enhances glutamine consumption via the TCA cycle. Metabolized glutamine generates itaconate which downregulates mitochondrial reactive oxygen species via regulation of Nrf2 and the oxidative stress response, enhancing MDSC survival. Using β2-AR blockade, we target the STAT3 pathway and ATP and itaconate metabolism, disrupting ATP generation by the electron transport chain and decreasing itaconate generation causing diminished MDSC mitochondrial fitness. This disruption increases the response to doxorubicin and could be tested clinically. Myeloid derived suppressor cells (MDSC) are associated with tumourigenesis and therapy response. Here, the authors show that beta 2-adrenergic receptor activation in MDSC leads to metabolic rewiring which regulates chemotherapy response in preclinical models of blood cancer.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-024-47096-9