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

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 ß2-adrenergic receptor (ß2-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 ß2-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. Overall design: WT and ß2AR-/- MDSCs were generated in vitro in presence of rmIL-6 and rmGM-CFS (40 ng/mL each) and 10 µM isoproterenol (ISO). On day 4, single cell libraries were generated using the 10X Genomics platform. First, Feature Barcode conjugated molecules were bound to cell surface proteins. Then live-CD11b+ cells were isolated using the SONY MA900 cell sorter (Sony Biotechnology). Sorted cells were subjected to scRNA-Seq.