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 ( < 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.

Novel direct AMPK activator suppresses non-small cell lung cancer through inhibition of lipid metabolism

“…However it not only bind to the α subunit but also the γ subunit [ 67 ]. The effect of OSU-53 was only examined in thyroid carcinoma and myeloid-derived suppressor cells [ 68 – 71 ]. Compound 13 was shown to inhibit hepatic lipid synthesis via an AMPK-dependent manner [ 72 ], and inhibit Helicobacter pylori-induced oxidative stresses leading to gastric epithelial cell apoptosis [ 73 ] but has not been tested in cancer cell yet.…”

The cellular metabolic landscape in the tumor milieu regulates the activity of myeloid infiltrates

“…Thus, although the role of AMPK has been well established in cancer cells, 62 the endogenous effect of AMPK on the modulation of tumorassociated myeloid cells remains unclear. Initial reports showed that pharmacological activation of AMPK blocked MDSC function in tumors, 68,69 while another study showed that AMPK signaling (1). AMPK phosphorylates ULK1, which promotes mitophagy and enhances mitochondrial function (2).…”

Guided migration analyses at the single-clone level uncover cellular targets of interest in tumor-associated myeloid-derived suppressor cell populations

“…Here we tested whether MDSCs respond to topographical cues by exhibiting structurally guided dissemination patterns similar to invasive cancerous cells. The murine MDSC cell line, MSC-2, was used as a model 6,24 . These cells were plated on microtextured polydimethylsiloxane (PDMS) surfaces ( Fig.…”