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Anti-inflammatory triterpenoid blocks immune suppressive function of MDSCs and improves immune response in cancer.

ABSTRACT: 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.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.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.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.

SUBMITTER: Nagaraj S

PROVIDER: S-EPMC2840181 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Anti-inflammatory triterpenoid blocks immune suppressive function of MDSCs and improves immune response in cancer.

Nagaraj Srinivas S 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

Clinical cancer research : an official journal of the American Association for Cancer Research 20100309 6

<h4>Purpose</h4>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.<h4>Experimental design</h4>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 ...[more]

PMID: 20215551

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Project description:Background and purposeSpontaneous intracerebral hemorrhage (sICH) is a common form of hemorrhagic stroke, with high mortality and morbidity. Pathophysiological mechanisms in sICH are poorly understood and treatments limited. Neuroinflammation driven by microglial-macrophage activation contributes to brain damage post-sICH. We aim to test the hypothesis that an anti-inflammatory (repair) process occurs in parallel with neuroinflammation in clinical sICH.MethodsWe performed quantitative analysis of immunohistochemical markers for microglia and macrophages (Iba1, CD68, TMEM119, CD163, and CD206) in brain tissue biospecimens 1 to 12 days post-sICH and matched control cases. In a parallel, prospective group of patients, we assayed circulating inflammatory markers (CRP [C-reactive protein], total white cell, and monocyte count) over 1 to 12 days following sICH.ResultsIn 27 supratentorial sICH cases (n=27, median [interquartile range] age: 59 [52–80.5], 14F/13M) all microglia-macrophage markers increased post-sICH, relative to control brains. Anti-inflammatory markers (CD163 and CD206) were elevated alongside proinflammatory markers (CD68 and TMEM119). CD163 increased progressively post-sICH (15.0-fold increase at 7–12 days, P<0.001). CD206 increased at 3 to 5 days (5.2-fold, P<0.001) then returned to control levels at 7 to 12 days. The parenchymal immune response combined brain-derived microglia (TMEM119 positive) and invading monocyte-derived macrophages (CD206 positive). In a prospective sICH patient cohort (n=26, age 74 [66–79], National Institutes of Health Stroke Scale on admission: 8 [4–17]; 14F/12M) blood CRP concentration and monocyte density (but not white blood cell) increased post-sICH. CRP increased from 0 to 2 to 3 to 5 days (8.3-fold, P=0.020) then declined at 7 to 12 days. Monocytes increased from 0 to 2 to 3 to 5 days (1.8-fold, P<0.001) then declined at 7 to 12 days.ConclusionsAn anti-inflammatory pathway, enlisting native microglia and blood monocytes, occurs alongside neuroinflammation post-sICH. This novel pathway offers therapeutic targets and a window of opportunity (3–5 days post-sICH) for delivery of therapeutics via invading monocytes.

Project description:BACKGROUND:Anthocyanins, one of the major plant bioactive substances, possess anti-oxidative and anti-inflammatory capacity. However, their dose-response relationship has remained unclear. The present study investigated the dose-response relationship of anthocyanins with oxidative stress and inflammation in subjects with dyslipidemia. DESIGN:and Participants: A total of 169 participants with dyslipidemia were randomly assigned to placebo (n = 43), anthocyanins 40 mg/day (n = 44), 80 mg/day (n = 40), or 320 mg/day (n = 42) groups. Urine 8-iso-prostaglandin F2? (8-iso-PGF2?), 8-hydroxy-2'-deoxyguanosine (8-OHdG) and serum malonaldehyde (MDA), total superoxide dismutase (T-SOD), UA (uric acid), interleukin (IL)-6, IL-10, tumor necrosis factor-? (TNF-?), and C-reactive protein (CRP) were measured at baseline, at 6 weeks, and at 12 weeks. RESULTS:Anthocyanin supplementation (320 mg/day) for 6 weeks significantly improved T-SOD versus baseline (P < 0.05). A slight reduction in serum IL-6, TNF-?, and urine 8-iso-PGF2? from the baseline was observed at 12 weeks in the group receiving 40 mg/day anthocyanins. Anthocyanins (80 mg/day) significantly reduced serum IL-6 (-20%), TNF-? (-11%) and urine 8-iso-PGF2? (-27%) versus baseline (P < 0.05). Moreover, 320 mg/day anthocyanin supplementation reduced serum IL-6 (-40%), TNF-? (-21%), MDA (-20%) and urine 8-iso-PGF2? (-37%) and 8-OHdG (-36%) than 80 mg/day and 40 mg/day anthocyanins, P value < 0.05. Anthocyanin supplementation has dose-response relationships with decreased inflammatory cytokines IL-6, TNF-? and oxidative stress biomarkers 8-iso-PGF2?, 8-OHdG and MDA (P for trend, <0.05). Furthermore, a strong positive correlation was observed between the changes in the urine 8-iso-PGF2? , 8-OHdG levels and serum IL-6 levels in subjects from anthocyanin groups after 12 weeks of treatment. CONCLUSIONS:Supplementation of anthocyanins for 12 weeks positively improved the anti-oxidative and anti-inflammatory capacity in a dose-response manner in individuals with dyslipidemia.

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Anti-inflammatory triterpenoid blocks immune suppressive function of MDSCs and improves immune response in cancer.

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Anti-inflammatory triterpenoid blocks immune suppressive function of MDSCs and improves immune response in cancer.

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