title: Targeting myeloid-derived suppressor cells using a novel adenosine monophosphate-activated protein kinase (AMPK) activator.
abstract: Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of early myeloid cells that accumulate in the blood and tumors of patients with cancer. MDSC play a critical role during tumor evasion and promote immune suppression through variety of mechanisms, such as the generation of reactive oxygen and nitrogen species (ROS and RNS) and cytokines. AMPactivated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase that regulates energy homeostasis and metabolic stress. However, the role of AMPK in the regulation of MDSC function remains largely unexplored. This study was designed to investigate whether treatment of MDSC with OSU-53, a PPAR-inactive derivative that stimulates AMPK kinase, can modulate MDSC function. Our results demonstrate that OSU-53 treatment increases the phosphorylation of AMPK, significantly reduces nitric oxide production, inhibits MDSC migration, and reduces the levels of IL-6 in murine MDSC cell line (MSC2 cells). OSU53 treatment mitigated the immune suppressive functions of murine MDSC, promoting T-cell proliferation. Although OSU-53 had a modest effect on tumor growth in mice inoculated with EMT-6 cells, importantly, administration of OSU53 significantly (p< 0.05) reduced the levels of MDSC in the spleens and tumors. Furthermore, mouse MDSC from EMT-6 tumor-bearing mice and human MDSC isolated from melanoma patients treated with OSU-53 showed a significant reduction in the expression of immune suppressive genes iNOS and arginase. In summary, these results demonstrate a novel role of AMPK in the regulation of MDSC functions and provide a rationale of combining OSU-53 with immune checkpoint inhibitors to augment their response in cancer patients.
authors.affiliation: Comprehensive Cancer Center, The Ohio State University , Columbus, OH, USA.
authors.forename: Prashant
authors.initials: P
authors.lastname: Trikha
authors.affiliation: Division of Surgical Oncology, Department of Surgery and Comprehensive Cancer Center, The Ohio State University , Columbus, OH, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Plews
authors.affiliation: Comprehensive Cancer Center, The Ohio State University , Columbus, OH, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Stiff
authors.affiliation: Comprehensive Cancer Center, The Ohio State University , Columbus, OH, USA.
authors.forename: Shalini
authors.initials: S
authors.lastname: Gautam
authors.affiliation: Comprehensive Cancer Center, The Ohio State University , Columbus, OH, USA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Hsu
authors.affiliation: Comprehensive Cancer Center, The Ohio State University , Columbus, OH, USA.
authors.forename: David
authors.initials: D
authors.lastname: Abood
authors.affiliation: Comprehensive Cancer Center, The Ohio State University , Columbus, OH, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Wesolowski
authors.affiliation: Comprehensive Cancer Center, The Ohio State University , Columbus, OH, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Landi
authors.affiliation: Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University , Columbus, OH, USA.
authors.forename: Xiaokui
authors.initials: X
authors.lastname: Mo
authors.affiliation: Division of Surgical Oncology, Department of Surgery and Comprehensive Cancer Center, The Ohio State University , Columbus, OH, USA.
authors.forename: John
authors.initials: J
authors.lastname: Phay
authors.affiliation: College of Pharmacy, The Ohio State University , Columbus, OH, USA.
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
authors.affiliation: Comprehensive Cancer Center, The Ohio State University , Columbus, OH, USA.
authors.forename: John
authors.initials: J
authors.lastname: Byrd
authors.affiliation: Comprehensive Cancer Center, The Ohio State University , Columbus, OH, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Caligiuri
authors.affiliation: Comprehensive Cancer Center, The Ohio State University , Columbus, OH, USA.
authors.forename: Susheela
authors.initials: S
authors.lastname: Tridandapani
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA; Division of Surgical Oncology, Department of Surgery and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: William
authors.initials: W
authors.lastname: Carson
keywords: AMPK; Immunotherapy; MDSC; OSU-53; iNOS