Immune regulatory effects of simvastatin on regulatory T cell-mediated tumour immune tolerance.
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)-beta and indoleamine-2,3-dioxygenase (IDO) by tumours, which induce a regulatory T cell (T(reg)) response. In this study, we investigated the effect of simvastatin on the production of IL-10, TGF-beta and IDO production and the proliferation of T(regs) 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-beta 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.
Lee
K J
KJ
Division of Respiratory and Critical Care Medicine, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea.
Moon
J Y
JY
Choi
H K
HK
Kim
H O
HO
Hur
G Y
GY
Jung
K H
KH
Lee
S Y
SY
Kim
J H
JH
Shin
C
C
Shim
J J
JJ
In
K H
KH
Yoo
S H
SH
Kang
K H
KH
Lee
S Y
SY
D000818:Animals; D002452:Cell Count; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D054697:Cytostatic Agents / Q000494:pharmacology / Q000627:therapeutic use; D051858:Forkhead Transcription Factors / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects* / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics; D016753:Interleukin-10 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D019821:Simvastatin / Q000494:pharmacology* / Q000627:therapeutic use; D013154:Spleen / Q000166:cytology / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
C530105:Ccnd1 protein, mouse; D054697:Cytostatic Agents; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C508018:Il2ra protein, mouse; D007166:Immunosuppressive Agents; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D053645:Interleukin-2 Receptor alpha Subunit; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D019938:Cyclin D1; D019821:Simvastatin