title: Differential immunomodulatory activity of tumor cell death induced by cancer therapeutic toll-like receptor ligands.
abstract: Synthetic toll-like receptor (TLR) ligands stimulate defined immune cell subsets and are currently tested as novel immunotherapeutic agents against cancer with, however, varying clinical efficacy. Recent data showed the expression of TLR receptors also on tumor cells. In this study we investigated immunological events associated with the induction of tumor cell death by poly(I:C) and imiquimod. A human head and neck squamous cell carcinoma (HNSCC) cell line was exposed to poly(I:C) and imiquimod, which were delivered exogenously via culture medium or via electroporation. Cell death and cell biological consequences thereof were analyzed. For in vivo analyses, a human xenograft and a syngeneic immunocompetent mouse model were used. Poly(I:C) induced cell death only if delivered by electroporation into the cytosol. Cell death induced by poly(I:C) resulted in cytokine release and activation of monocytes in vitro. Monocytes activated by the supernatant of cancer cells previously exposed to poly(I:C) recruited significantly more Th1 cells than monocytes exposed to control supernatants. If delivered exogenously, imiquimod also induced tumor cell death and some release of interleukin-6, but cell death was not associated with release of Th1 cytokines, interferons, monocyte activation and Th1 recruitment. Interestingly, intratumoral injection of poly(I:C) triggered tumor cell death in tumor-bearing mice and reduced tumor growth independent of TLR signaling on host cells. Imiquimod did not affect tumor size. Our data suggest that common cancer therapeutic RNA compounds can induce functionally diverse types of cell death in tumor cells with implications for the use of TLR ligands in cancer immunotherapy.
authors.affiliation: Department of Otorhinolaryngology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany.|Research Division, Department of Otorhinolaryngology, University of Duisburg-Essen, Hufelandstraße 55, 45122, Essen, Germany.
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Klein
authors.affiliation: Department of Otorhinolaryngology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany.|Research Division, Department of Otorhinolaryngology, University of Duisburg-Essen, Hufelandstraße 55, 45122, Essen, Germany.
authors.forename: Clarissa A
authors.initials: CA
authors.lastname: Wild
authors.affiliation: Department of Otorhinolaryngology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Lang
authors.affiliation: Department of Otorhinolaryngology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany. sven.brandau@uk-essen.de.|Research Division, Department of Otorhinolaryngology, University of Duisburg-Essen, Hufelandstraße 55, 45122, Essen, Germany. sven.brandau@uk-essen.de.
authors.forename: Sven
authors.initials: S
authors.lastname: Brandau
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D054357:Chemokine CXCL10 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology; D056747:Immunomodulation; D018836:Inflammation Mediators / Q000378:metabolism; D008024:Ligands; D016131:Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D011070:Poly I-C / Q000494:pharmacology; D051193:Toll-Like Receptors / Q000378:metabolism*
chemical_list: D054357:Chemokine CXCL10; D016207:Cytokines; D015395:Histocompatibility Antigens Class I; D007155:Immunologic Factors; D018836:Inflammation Mediators; D008024:Ligands; D051193:Toll-Like Receptors; D011070:Poly I-C
keywords: CXCL-10; HNSCC; Immunogenic tumor cell death; T-helper 1 immunity; TLR ligand