Anti-inflammatory Triterpenoid Blocks Immune Suppressive Function of MDSCs and Improves Immune Response in Cancer
- 14 March 2010
- journal article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 16 (6), 1812-1823
- https://doi.org/10.1158/1078-0432.ccr-09-3272
Abstract
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. Clin Cancer Res; 16(6); 1812–23Keywords
Other Versions
This publication has 43 references indexed in Scilit:
- Myeloid-derived suppressor cells as regulators of the immune systemNature Reviews Immunology, 2009
- CDDO-Me, a synthetic triterpenoid, inhibits expression of IL-6 and Stat3 phosphorylation in multi-drug resistant ovarian cancer cellsCancer Chemotherapy and Pharmacology, 2008
- Triterpenoid CDDO-Methyl Ester Inhibits the Janus-Activated Kinase-1 (JAK1)→Signal Transducer and Activator of Transcription-3 (STAT3) Pathway by Direct Inhibition of JAK1 and STAT3Cancer Research, 2008
- Arginine regulation by myeloid derived suppressor cells and tolerance in cancer: mechanisms and therapeutic perspectivesImmunological Reviews, 2008
- Signaling defects in anti‐tumor T cellsImmunological Reviews, 2008
- Amino-Biphosphonate–Mediated MMP-9 Inhibition Breaks the Tumor-Bone Marrow Axis Responsible for Myeloid-Derived Suppressor Cell Expansion and Macrophage Infiltration in Tumor StromaCancer Research, 2007
- Preclinical Evaluation of Targeting the Nrf2 Pathway by Triterpenoids (CDDO-Im and CDDO-Me) for Protection from LPS-Induced Inflammatory Response and Reactive Oxygen Species in Human Peripheral Blood Mononuclear Cells and NeutrophilsAntioxidants and Redox Signaling, 2007
- Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancerNature Medicine, 2007
- Triterpenoids and rexinoids as multifunctional agents for the prevention and treatment of cancerNature Reviews Cancer, 2007
- All-trans-Retinoic Acid Improves Differentiation of Myeloid Cells and Immune Response in Cancer PatientsCancer Research, 2006