title: Langerhans cells and dendritic cells are cytotoxic towards HPV16 E6 and E7 expressing target cells.
abstract: Dendritic cells (DC) can be cytotoxic towards tumor cells by means of TNF family molecules expressed on the cell surface of activated DCs. Tumor cells expressing appropriate receptors are killed by DC, generating a source of antigen to be presented to the immune system. It has not been investigated whether Langerhans cells (LC) are selectively cytotoxic to tumor cells. This is of particular interest for epithelial tumor cells that physically interact with LC in vivo. Among epithelial tumors, the oncogenic process of cervical tumors is relatively well defined by their Human Papillomavirus (HPV) mediated etiology. To study whether HPV16 E6 and E7 expressions, otherwise observed in cervical tumor cells, can sensitize normal cervical epithelial cells to DC and LC mediated killing, the E6 and E7 genes were introduced by retroviral transfection, and cells were subsequently used as targets in cytotoxicity assays. Expression of cytotoxic molecules by effector cells was measured in response to the pro-inflammatory cytokine IFN-gamma; cytotoxicity was established and concomitant expression of receptor molecules was assessed on target cells. A correlation between the shrinkage of HPV16 E6 and E7+ tumors versus DC and LC infiltration was evaluated in a murine model of cervical cancer. DC and LC proved to be equally cytotoxic towards E6 and E7 expressing cervical epithelial cells. IFN-gamma induced TRAIL expression by DC and LC, and inhibition of TRAIL partially blocked cytotoxic effects. Expression of TRAIL decoy receptors was reduced following introduction of E6 and E7 into host cells. Shrinkage of HPV16 E6 and E7 expressing tumors correlated with infiltration by S100+ DC and LC, co-localizing with apoptotic mouse tumor cells. In conclusion, DC and LC mediated killing may be exploitable for anti-tumor treatment.
authors.affiliation: Department of Pathology/Oncology Institute, Loyola University Medical Center, Bldg 112, Rm 203, 2160 South 1st Ave, Maywood, IL 60153, USA. ilepool@lumc.edu
authors.forename: I Caroline
authors.initials: IC
authors.lastname: Le Poole
authors.forename: Wafic M
authors.initials: WM
authors.lastname: ElMasri
authors.forename: Cecele J
authors.initials: CJ
authors.lastname: Denman
authors.forename: Tara M
authors.initials: TM
authors.lastname: Kroll
authors.forename: Hemamalini
authors.initials: H
authors.lastname: Bommiasamy
authors.forename: Gretchen
authors.initials: G
authors.lastname: Lyons Eiben
authors.forename: W Martin
authors.initials: WM
authors.lastname: Kast
mesh_terms: D000818:Animals; D017209:Apoptosis; D003713:Dendritic Cells / Q000166:cytology* / Q000821:virology*; D005260:Female; D015967:Gene Expression Regulation, Viral; D006801:Humans; D007107:Immune System; D007167:Immunotherapy / Q000379:methods*; D007249:Inflammation; D007801:Langerhans Cells / Q000166:cytology* / Q000821:virology*; D051379:Mice; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000473:pathology
chemical_list: C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C059731:oncogene protein E7, Human papillomavirus type 16