Anti-inflammatory triterpenoid blocks immune suppressive function of MDSCs and improves immune response in cancer.
OBJECTIVE
Myeloid-derived suppressor cells (MDSC) are one of the major factors responsible for immune suppression in cancer. Therefore, it would be important to identify effective therapeutic means to modulate these cells.


METHODS
We evaluated the effect of the synthetic triterpenoid C-28 methyl ester of 2-cyano-3,12-dioxooleana-1,9,-dien-28-oic acid (CDDO-Me; bardoxolone methyl) in MC38 colon carcinoma, Lewis lung carcinoma, and EL-4 thymoma mouse tumor models, as well as blood samples from patients with renal cell cancer and soft tissue sarcoma. Samples were also analyzed from patients with pancreatic cancer treated with CDDO-Me in combination with gemcitabine.


RESULTS
CDDO-Me at concentrations of 25 to 100 nmol/L completely abrogated immune suppressive activity of MDSC in vitro. CDDO-Me reduced reactive oxygen species in MDSCs but did not affect their viability or the levels of nitric oxide and arginase. Treatment of tumor-bearing mice with CDDO-Me did not affect the proportion of MDSCs in the spleens but eliminated their suppressive activity. This effect was independent of antitumor activity. CDDO-Me treatment decreased tumor growth in mice. Experiments with severe combined immunodeficient-beige mice indicated that this effect was largely mediated by the immune system. CDDO-Me substantially enhanced the antitumor effect of a cancer vaccines. Treatment of pancreatic cancer patients with CDDO-Me did not affect the number of MDSCs in peripheral blood but significantly improved the immune response.


CONCLUSIONS
CDDO-Me abrogated the immune suppressive effect of MDSCs and improved immune responses in tumor-bearing mice and cancer patients. It may represent an attractive therapeutic option by enhancing the effect of cancer immunotherapy.
Nagaraj
Srinivas
S
H. Lee Moffitt Cancer Center, Tampa, Florida 33647, USA.
Youn
Je-In
JI
Weber
Hannah
H
Iclozan
Cristina
C
Lu
Lily
L
Cotter
Matthew J
MJ
Meyer
Colin
C
Becerra
Carlos R
CR
Fishman
Mayer
M
Antonia
Scott
S
Sporn
Michael B
MB
Liby
Karen T
KT
Rawal
Bhupendra
B
Lee
Ji-Hyun
JH
Gabrilovich
Dmitry I
DI
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001119:Arginase / Q000378:metabolism; D017321:Clinical Trials, Phase I as Topic; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008875:Middle Aged; D022423:Myeloid Cells / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D011379:Prognosis; D017382:Reactive Oxygen Species / Q000378:metabolism
D007166:Immunosuppressive Agents; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D009828:Oleanolic Acid; C445068:bardoxolone methyl; D001119:Arginase