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

ABSTRACT: Myeloid-derived suppressor cells mitochondrial fitness governs chemotherapeutic efficacy in hematologic malignancies

PROVIDER: PRJNA1070688 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27766130.fastq.gz	Fastqsanger.gz
	SRR27766131.fastq.gz	Fastqsanger.gz
	SRR27766132.fastq.gz	Fastqsanger.gz
	SRR27766133.fastq.gz	Fastqsanger.gz

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

Project description:Myeloid derived suppressor cells (MDSCs) are key regulators of immune responses and correlated with poor outcomes in hematologic malignancies. Here, we identify the mitochondrial fitness in MDSCs controlling the efficacy of doxorubicin chemotherapy for lymphoma. Mechanistically, we show that triggering STAT3 signaling via β2-adrenergic receptor (β2-AR) activation leads to metabolic reprograming of MDSCs, marked by sustained mitochondrial respiration (OX/PHOS) and higher ATP generation which reduces the AMPK signaling. Furthermore, induced STAT3 signaling in MDSCs enhanced glutamine consumption via the tricarboxylic acid (TCA) cycle. Metabolized glutamine generates itaconate which downregulates mitochondrial reactive oxygen species (mROS) via regulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and the antioxidant machinery. We found that targeting the STAT3 pathway or ATP/Itaconate metabolites by blocking β2-AR signaling, the electron transport chain and ATP generation, or itaconate generation, results in disrupted MDSC mitochondrial fitness. This disruption increases the in vivo response to doxorubicin, delaying lymphoma progression.

2024-02-29 | GSE254512 | GEO

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

Project description: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.

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