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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Oncoimmunology
2016 ; 5
(9
): e1214787
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Targeting myeloid-derived suppressor cells using a novel adenosine
monophosphate-activated protein kinase (AMPK) activator
#MMPMID27757311
Trikha P
; Plews RL
; Stiff A
; Gautam S
; Hsu V
; Abood D
; Wesolowski R
; Landi I
; Mo X
; Phay J
; Chen CS
; Byrd J
; Caligiuri M
; Tridandapani S
; Carson W
Oncoimmunology
2016[]; 5
(9
): e1214787
PMID27757311
show ga
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.