TLR7 and TLR8 as targets in cancer therapy

被引:256
作者
Schoen, M. P. [1 ,2 ]
Schoen, M. [1 ,2 ]
机构
[1] Univ Wurzburg, Rudolf Virchow Ctr, DFG Res Ctr Expt Biomed, D-97078 Wurzburg, Germany
[2] Univ Wurzburg, Dept Dermatol, D-97078 Wurzburg, Germany
关键词
TLR7; TLR8; skin cancer; imiquimod; imidazoquinolines; cancer immunity;
D O I
10.1038/sj.onc.1210913
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Small-molecule agonists at Toll-like receptor 7 (TLR7) and TLR8 have sparked a vivid interest in cancer research owing to their profound antitumoral activity. The lead compound of the imidazoquinoline family, imiquimod, is marketed as a topical formulation. It is efficacious against many primary skin tumors and cutaneous metastases. Using different imidazoquinoline species, distinct functions of TLR7 and TLR8 have been discovered. The predominant antitumoral mode of action of these agents is TLR7/8-mediated activation of the central transcription factor nuclear factor-kappa B, which leads to induction of proinflammatory cytokines and other mediators. Cutaneous dendritic cells are the primary responsive cell type and initiate a strong Th1-weighted antitumoral cellular immune response. Recent research has shown that dendritic cells themselves acquire direct antitumoral activity upon stimulation by imiquimod. In addition, there are a number of secondary effects on the molecular and cellular level that can be explained through the activation of TLR7/8. The proinflammatory activity of imiquimod, but not resiquimod, appears to be augmented by suppression of a regulatory mechanism, which normally limits inflammatory responses. This is achieved independently of TLR7/8 through interference with adenosine receptor signaling pathways. Finally, at higher concentrations imiquimod exerts Bcl-2- and caspase-dependent proapoptotic activity against tumor cells.
引用
收藏
页码:190 / 199
页数:10
相关论文
共 114 条
[1]   Imiquimod, a Toll-like receptor-7 agonist, induces perforin in cytotoxic T lymphocytes in vitro [J].
Ambach, A ;
Bonnekoh, B ;
Nguyen, M ;
Schön, MP ;
Gollnick, H .
MOLECULAR IMMUNOLOGY, 2004, 40 (18) :1307-1314
[2]   Imiquimod-induced interleukin-1α stimulation improves barrier homeostasis in aged murine epidermis [J].
Barland, CO ;
Zettersten, E ;
Brown, BS ;
Ye, JQ ;
Elias, PM ;
Ghadially, R .
JOURNAL OF INVESTIGATIVE DERMATOLOGY, 2004, 122 (02) :330-336
[3]   Interventions for basal cell carcinoma of the skin: systematic review [J].
Bath-Hextall, F ;
Bong, J ;
Perkins, W ;
Williams, H .
BMJ-BRITISH MEDICAL JOURNAL, 2004, 329 (7468) :705-708
[4]   Expression of Fas-receptor on basal cell carcinomas after treatment with imiquimod 5% cream or vehicle [J].
Berman, B ;
Sullivan, T ;
De Araujo, T ;
Nadji, M .
BRITISH JOURNAL OF DERMATOLOGY, 2003, 149 :59-61
[5]   EFFECT OF IMIQUIMOD AS AN ADJUVANT FOR IMMUNOTHERAPY OF GENITAL HSV IN GUINEA-PIGS [J].
BERNSTEIN, DI ;
HARRISON, CJ ;
TEPE, ER ;
SHAHWAN, A ;
MILLER, RL .
VACCINE, 1995, 13 (01) :72-76
[6]  
BERSTEIN DI, 2000, J INFECT DIS, V183, P844
[7]   The immune response modifier resiquimod mimics CD40-induced B cell activation [J].
Bishop, GA ;
Ramirez, LM ;
Baccam, M ;
Busch, LK ;
Pederson, LK ;
Tomai, MA .
CELLULAR IMMUNOLOGY, 2001, 208 (01) :9-17
[8]   Imiquimod, a topical immune response modifier, in the treatment of cutaneous metastases of malignant melanoma [J].
Bong, AB ;
Bonnekoh, B ;
Franke, I ;
Schön, MP ;
Ulrich, J ;
Gollnick, H .
DERMATOLOGY, 2002, 205 (02) :135-138
[9]   The immune response modifier imiquimod requires STAT-1 for induction of interferon, interferon-stimulated genes, and interleukin-6 [J].
Bottrel, RLA ;
Yang, YL ;
Levy, DE ;
Tomai, M ;
Reis, LFL .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 1999, 43 (04) :856-861
[10]   Safety and efficacy of 5% imiquimod cream for the treatment of skin dysplasia in high-risk renal transplant recipients - Randomized, double-blind, placebo-controlled trial [J].
Brown, VL ;
Atkins, CL ;
Ghali, L ;
Cerio, R ;
Harwood, CA ;
Proby, CM .
ARCHIVES OF DERMATOLOGY, 2005, 141 (08) :985-993