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

Saeed Daneshmandi, Jee Eun Choi, Qi Yan, Cameron R. MacDonald, Manu Pandey, Mounika Goruganthu, Nathan Roberts, Prashant K. Singh, Richard M. Higashi, Andrew N. Lane, Teresa W-M. Fan, Jianmin Wang, Philip L. McCarthy, Elizabeth A. Repasky and Hemn Mohammadpour ()
Additional contact information
Saeed Daneshmandi: Roswell Park Comprehensive Cancer Center, Buffalo
Jee Eun Choi: Roswell Park Comprehensive Cancer Center, Buffalo
Qi Yan: Roswell Park Comprehensive Cancer Center, Buffalo
Cameron R. MacDonald: Roswell Park Comprehensive Cancer Center, Buffalo
Manu Pandey: Roswell Park Comprehensive Cancer Center, Buffalo
Mounika Goruganthu: Roswell Park Comprehensive Cancer Center, Buffalo
Nathan Roberts: Roswell Park Comprehensive Cancer Center, Buffalo
Prashant K. Singh: Roswell Park Comprehensive Cancer Center, Buffalo
Richard M. Higashi: Center for Environmental and Systems Biochemistry (CESB)
Andrew N. Lane: Center for Environmental and Systems Biochemistry (CESB)
Teresa W-M. Fan: Center for Environmental and Systems Biochemistry (CESB)
Jianmin Wang: Roswell Park Comprehensive Cancer Center, Buffalo
Philip L. McCarthy: Roswell Park Comprehensive Cancer Center, Buffalo
Elizabeth A. Repasky: Roswell Park Comprehensive Cancer Center, Buffalo
Hemn Mohammadpour: Roswell Park Comprehensive Cancer Center, Buffalo

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-47096-9

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