Immune regulatory effects of simvastatin on regulatory T cell-mediated tumour immune tolerance
Open Access
- 18 May 2010
- journal article
- research article
- Published by Oxford University Press (OUP) in Clinical and Experimental Immunology
- Vol. 161 (2), 298-305
- https://doi.org/10.1111/j.1365-2249.2010.04170.x
Abstract
Statins are potent inhibitors of hydroxyl‐3‐methylglutaryl co‐enzyme A (HMG‐CoA) reductase, and have emerged as potential anti‐cancer agents based on preclinical evidence. In particular, compelling evidence suggests that statins have a wide range of immunomodulatory properties. However, little is known about the role of statins in tumour immune tolerance. Tumour immune tolerance involves the production of immunosuppressive molecules, such as interleukin (IL)‐10, transforming growth factor (TGF)‐β and indoleamine‐2,3‐dioxygenase (IDO) by tumours, which induce a regulatory T cell (Treg) response. In this study, we investigated the effect of simvastatin on the production of IL‐10, TGF‐β and IDO production and the proliferation of Tregs using several cancer cell lines, and Lewis lung cancer (3LL) cells‐inoculated mouse tumour model. Simvastatin treatment resulted in a decrease in the number of cancer cells (3LL, A549 and NCI‐H292). The production of the immune regulatory markers IL‐10, TGF‐β in 3LL and NCI‐H292 cells increased after treatment with simvastatin. The expression of IDO and forkhead box P3 (FoxP3) transcription factor was also increased in the presence of simvastatin. In a murine 3LL model, there were no significant differences in tumour growth rate between untreated and simvastatin‐treated mice groups. Therefore, while simvastatin had an anti‐proliferative effect, it also exhibited immune tolerance‐promoting properties during tumour development. Thus, due to these opposing actions, simvastatin had no net effect on tumour growth.This publication has 35 references indexed in Scilit:
- The effect of HMG-CoA reductase inhibitors on naturally occurring CD4+CD25+ T cellsAtherosclerosis, 2008
- Foxp3 Expression in Pancreatic Carcinoma Cells as a Novel Mechanism of Immune Evasion in CancerCancer Research, 2007
- Modulation of tryptophan catabolism by human leukemic cells results in the conversion of CD25− into CD25+ T regulatory cellsBlood, 2006
- Anti-Inflammatory Effects of Statins: Clinical Evidence and Basic MechanismsNature Reviews Drug Discovery, 2005
- Regulatory T Cell Lineage Specification by the Forkhead Transcription Factor Foxp3Immunity, 2005
- Anti-inflammatory and immunomodulatory effects of statinsKidney International, 2003
- The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune diseaseNature, 2002
- A novel adenoviral vector expressing human Fas/CD95/APO-1 enhances p53-mediated apoptosisCell Death & Differentiation, 1999
- Inhibition of proinflammatory cytokine production by pravastatinThe Lancet, 1999
- Prevention of Cardiovascular Events and Death with Pravastatin in Patients with Coronary Heart Disease and a Broad Range of Initial Cholesterol LevelsThe New England Journal of Medicine, 1998