Toll-like Receptor 3 Expressed by Melanoma Cells as a Target for Therapy?

• Published in: Clinical cancer research Vol. 13; no. 15; pp. 4565 - 4574
• Main Authors: SALAUN, Bruno, LEBECQUE, Serge, MATIKAINEN, Sampsa, RIMOLDI, Donata, ROMERO, Pedro
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-08-2007
• Subjects: Antineoplastic agents; Apoptosis - immunology; Biological and medical sciences; Caspases - metabolism; Cell Death and Senescence; Cell Proliferation; Dermatology; Humans; Immunology; Immunoprecipitation; Interferon-alpha - pharmacology; Lentivirus - genetics; Medical sciences; Melanoma - metabolism; Melanoma - pathology; Melanoma - therapy; Melanoma/skin cancers; Novel mechanisms; Pharmacology. Drug treatments; Poly I-C - pharmacology; RNA Interference; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; Skin Neoplasms - therapy; Toll-Like Receptor 3 - agonists; Toll-Like Receptor 3 - metabolism; Tumors of the skin and soft tissue. Premalignant lesions; Malignant tumor; Target cell; Toll like receptor 3; Gene expression; Targeted therapy; Malignant melanoma
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-07-0274

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.