Immunomodulatory effects of Toll-like receptor-7 activation on chronic lymphocytic leukemia cells.
Weak immunogenicity of chronic lymphocytic leukemia (CLL) cells may contribute to disease progression and inhibit effective immunotherapy. Accordingly, agents that enhance the immunogenicity of CLL cells may be useful in immunotherapeutic approaches to this disease. Since Toll-like receptors (TLRs) are major regulators of innate immunity and initiation of adaptive immunity, we studied the effects of viral pathogen associated molecular pattern agonists (that are recognized by TLRs) on the costimulatory phenotype and function of CLL cells. CLL cells (especially those with high endogenous expression of CD38) responded to TLR7-activating imidazoquinolines and guanosine analogs by increasing costimulatory molecule expression, producing inflammatory cytokines, and becoming more sensitive to killing by cytotoxic effectors. Additional activation of protein kinase C pathways increased the ability to stimulate T-cell proliferation, blocked phosphorylation of the transcription factor, signal transducer and activator of transcription (STAT)3, and resulted in the acquisition of a dendritic cell surface phenotype by TLR7-activated CLL cells. Normal B cells also responded to TLR7 activation by increasing costimulatory molecule expression and cytokine production. These findings suggest a potential role for TLR7 agonists in CLL immunotherapy.
Spaner
D E
DE
Division of Molecular and Cellular Biology, Research Institute, Sunnybrook and Women's College Health Sciences Center, Toronto, Canada. spanerd@srcl.sunnybrook.utoronto.ca
Shi
Y
Y
White
D
D
Mena
J
J
Hammond
C
C
Tomic
J
J
He
L
L
Tomai
M A
MA
Miller
R L
RL
Booth
J
J
Radvanyi
L
L
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007155:Immunologic Factors / Q000494:pharmacology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010703:Phorbol Esters / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000187:drug effects / Q000378:metabolism; D012680:Sensitivity and Specificity; D051199:Toll-Like Receptor 7 / Q000187:drug effects / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D018925:Chemokines; D016207:Cytokines; D007093:Imidazoles; D007155:Immunologic Factors; D010703:Phorbol Esters; D011804:Quinolines; C508708:S 28690; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7