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 reprogram- ing, 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 gen- eration 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.
Document Type
Article
Publication Date
3-30-2024
Digital Object Identifier (DOI)
https://doi.org/10.1038/s41467-024-47096-9
Funding Information
The authors thank Jeanne M. Prendergast, Feng Li, Eugene Kononov, Courtney C. Ryan, and Suzanne M. Hess, for technical assistance and support, and the Genomics Shared Resource, Translational Imaging Shared Resource, Comparative Oncology Shared Resources (COSR), and the Flow Cytometry Core Facility for expert support. MS were recorded using the Metabolism Shared Resources at the University of Kentucky supported in part by P30CA177558 (to B.M. Evers). This project is supported by K99 HL155792, R00 HL155792, and Roswell Park Alliance Foundation (to H.M.), R01 CA205246 (to E.R.), F30CA265127 (to C.R.M.), and a donation from Brendan and Elise McCarthy (P.L.M.), and NCI grant P30CA016056.
Repository Citation
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.; and Mohammadpour, Hemn, "Myeloid-derived suppressor cell mitochondrial fitness governs chemotherapeutic efficacy in hematologic malignancies" (2024). Markey Cancer Center Faculty Publications. 218.
https://uknowledge.uky.edu/markey_facpub/218
Included in
Biochemistry Commons, Genetics Commons, Molecular Biology Commons, Oncology Commons, Other Chemistry Commons, Other Physics Commons
Notes/Citation Information
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/ licenses/by/4.0/. © The Author(s) 2024