Toll-like receptor 3 expressed by melanoma cells as a target for therapy?

被引:173
作者
Salaun, Bruno
Lebecque, Serge
Matikainen, Sampsa
Rimoldi, Donata
Romero, Pedro
机构
[1] Ludwig Inst Canc Res, CH-1066 Epalinges, Switzerland
[2] Univ Lyon 1, Inst Natl Sante Rech Med, U503 IFR128, F-69365 Lyon, France
[3] Finnish Inst Occupat Hlth, Unit Excellence Immunotoxicol, Helsinki, Finland
关键词
DOUBLE-STRANDED-RNA; POLYADENYLIC-POLYURIDYLIC ACID; INDUCED APOPTOSIS; SIGNALING COMPLEXES; INTERFERON-BETA; INNATE IMMUNITY; IFN-BETA; KAPPA-B; ACTIVATION; RESPONSES;
D O I
10.1158/1078-0432.CCR-07-0274
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: The immunomodulatory properties of Toll-like receptors (TLR) agonists have inspired their use as experimental adjuvants for vaccination of cancer patients. However, it is now well recognized that TLR expression is not restricted to immune cells but can also be found in many cell types, including those giving rise to tumors. It is therefore mandatory to explore the potential effects of TLR triggering directly on tumor cells. Experimental Design: In the present work, we have investigated TLR3 protein expression in melanoma cell lines derived from patients, and analyzed the effects of TLR3 agonists on tumor cell survival. Moreover, we used RNA interference to stably knock down TLR3 expression and study the involvement of this receptor in dsRNA-induced effects on melanoma cells viability. Results: Human melanoma cells can express functional TLR3 protein. Interestingly, the engagement of the receptor by TLR3 agonists can directly inhibit cell proliferation and induce tumor cell death when combined to treatment with either type I IFN or protein synthesis inhibitors. These effects were shown by RNA interference to be largely dependent on TLR3, Moreover, TLR3-mediated cell death involves the activation of caspases and engages both extrinsic and intrinsic apoptotic pathways. Conclusion: TLR3 protein can be expressed in human melanoma cells, where it can deliver proapoptotic and antiproliferative signaling. Altogether, these results suggest that TLR3 agonists represent very promising adjuvants for cancer vaccines not only based on their well-described immunostimulatory properties, but also due to their newly identified cytostatic and cytotoxic effects directly on tumor cells.
引用
收藏
页码:4565 / 4574
页数:10
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