TLR stimulation of prostate tumor cells induces chemokine-mediated recruitment of specific immune cell types.
TLRs boost antimicrobial response mechanisms by epithelial cells and represent the first line of defense at mucosal sites. In view of these immunomodulatory properties, TLR stimulation may represent a novel means to activate anticancer immune responses. In the present study, the ability of TLR ligands to affect the recruitment of different immune cell populations by human prostate cancer cell lines and the underlying mechanisms were investigated. We showed that LNCaP and DU-145 cells express functionally active TLR3 and TLR5. Treatment with their respective agonists, polyinosinic:polycytidylic acid and flagellin, rapidly triggered NF-kappaB-dependent upregulation of different inflammatory molecules, as assayed by microarray and ELISA. Furthermore, we demonstrated that conditioned media from polyinosinic:polycytidylic acid- and flagellin-treated LNCaP and DU-145 cells induced the recruitment of different leukocyte subpopulations, suggesting that TLR stimulation is able to activate the earliest step of immune response mediated by soluble factors. Interestingly, the more aggressive cancer cell line PC3 expressed TLR3 and TLR5 but failed to respond to TLR agonists in terms of NF-kappaB activation and the ability to attract immune effectors. Overall, these data show for the first time that TLR3 and TLR5 stimulation of human prostate cancer cells triggers the production of chemokines, which, in turn, favor the attraction of immune effectors, thereby representing a tool to enhance the efficacy of conventional therapies by stimulating anticancer immune responses.
Galli
Roberta
R
Department of Histology and Medical Embryology, Institute Pasteur-Foundation Cenci Bolognetti, Sapienza University of Rome, Rome, Italy.
Starace
Donatella
D
Busà
Roberta
R
Angelini
Daniela F
DF
Paone
Alessio
A
De Cesaris
Paola
P
Filippini
Antonio
A
Sette
Claudio
C
Battistini
Luca
L
Ziparo
Elio
E
Riccioli
Anna
A
D015153:Blotting, Western; D045744:Cell Line, Tumor; D018925:Chemokines / Q000276:immunology* / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D008297:Male; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000276:immunology* / Q000378:metabolism; D051198:Toll-Like Receptor 5 / Q000276:immunology* / Q000378:metabolism
D018925:Chemokines; D016328:NF-kappa B; D012333:RNA, Messenger; C495344:TLR3 protein, human; C495346:TLR5 protein, human; D051196:Toll-Like Receptor 3; D051198:Toll-Like Receptor 5