Triggering of TLR7 and TLR8 expressed by human lung cancer cells induces cell survival and chemoresistance.
Compelling evidence suggests that inflammation, cell survival, and cancer are linked, with a central role played by NF-kappaB. Recent studies implicate some TLRs in tumor development based on their ability to facilitate tumor growth; however, to our knowledge, involvement of neither TLR7 nor TLR78 has yet been demonstrated. Here we have demonstrated expression of TLR7 and TLR8, the natural receptors for single-stranded RNA, by tumor cells in human lung cancer in situ and in human lung tumor cell lines. Stimulation with TLR7 or TLR8 agonists led to activated NF-kappaB, upregulated expression of the antiapoptotic protein Bcl-2, increased tumor cell survival, and chemoresistance. Transcriptional analysis performed on human primary lung tumor cells and TLR7- or TLR8-stimulated human lung tumor cell lines revealed a gene expression signature suggestive of chronic stimulation of tumor cells by TLR ligands in situ. Together, these data emphasize that TLR signaling can directly favor tumor development and further suggest that researchers developing anticancer immunotherapy using TLR7 or TLR8 agonists as adjuvants should take into account the expression of these TLRs in lung tumor cells.
Cherfils-Vicini
Julien
J
INSERM U872, Centre de Recherche des Cordeliers, Paris, France.
Platonova
Sophia
S
Gillard
Mélanie
M
Laurans
Ludivine
L
Validire
Pierre
P
Caliandro
Rafaele
R
Magdeleinat
Pierre
P
Mami-Chouaib
Fathia
F
Dieu-Nosjean
Marie-Caroline
MC
Fridman
Wolf-Herman
WH
Damotte
Diane
D
Sautès-Fridman
Catherine
C
Cremer
Isabelle
I
D045744:Cell Line, Tumor; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D006151:Guanosine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D053583:Interleukin-1beta / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction; D051199:Toll-Like Receptor 7 / Q000032:analysis / Q000502:physiology*; D051200:Toll-Like Receptor 8 / Q000032:analysis / Q000502:physiology*
D053583:Interleukin-1beta; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; C495348:TLR7 protein, human; C495349:TLR8 protein, human; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D006151:Guanosine; C068562:loxoribine