PURPOSE: 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. EXPERIMENTAL DESIGN: 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.
PURPOSE: 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. EXPERIMENTAL DESIGN: 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-4thymoma 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 cancerpatients 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 cancerpatients. It may represent an attractive therapeutic option by enhancing the effect of cancer immunotherapy.
Authors: Yulia Nefedova; Srinivas Nagaraj; Amsler Rosenbauer; Carlos Muro-Cacho; Said M Sebti; Dmitry I Gabrilovich Journal: Cancer Res Date: 2005-10-15 Impact factor: 12.701
Authors: Jennifer S Ko; Arnold H Zea; Brian I Rini; Joanna L Ireland; Paul Elson; Peter Cohen; Ali Golshayan; Patricia A Rayman; Laura Wood; Jorge Garcia; Robert Dreicer; Ronald Bukowski; James H Finke Journal: Clin Cancer Res Date: 2009-03-10 Impact factor: 12.531
Authors: Zhenfeng Duan; Rachel Y Ames; Meagan Ryan; Francis J Hornicek; Henry Mankin; Michael V Seiden Journal: Cancer Chemother Pharmacol Date: 2008-06-28 Impact factor: 3.333
Authors: Kiavash Movahedi; Martin Guilliams; Jan Van den Bossche; Rafael Van den Bergh; Conny Gysemans; Alain Beschin; Patrick De Baetselier; Jo A Van Ginderachter Journal: Blood Date: 2008-02-13 Impact factor: 22.113
Authors: Karen Liby; Renee Risingsong; Darlene B Royce; Charlotte R Williams; Mark M Yore; Tadashi Honda; Gordon W Gribble; William W Lamph; Nicola Vannini; Ilaria Sogno; Adriana Albini; Michael B Sporn Journal: Clin Cancer Res Date: 2008-07-15 Impact factor: 12.531
Authors: Vitali Alexeev; Elizabeth Lash; April Aguillard; Laura Corsini; Avi Bitterman; Keith Ward; Adam P Dicker; Alban Linnenbach; Ulrich Rodeck Journal: Mol Cancer Ther Date: 2014-11-14 Impact factor: 6.261
Authors: Ciric To; Carol S Ringelberg; Darlene B Royce; Charlotte R Williams; Renee Risingsong; Michael B Sporn; Karen T Liby Journal: Carcinogenesis Date: 2015-05-04 Impact factor: 4.944
Authors: Jeremy D Waight; Colleen Netherby; Mary L Hensen; Austin Miller; Qiang Hu; Song Liu; Paul N Bogner; Matthew R Farren; Kelvin P Lee; Kebin Liu; Scott I Abrams Journal: J Clin Invest Date: 2013-09-16 Impact factor: 14.808
Authors: Megan M Blewett; Jiji Xie; Balyn W Zaro; Keriann M Backus; Amnon Altman; John R Teijaro; Benjamin F Cravatt Journal: Sci Signal Date: 2016-09-13 Impact factor: 8.192