title: Langerhans cells from women with cervical precancerous lesions become functionally responsive against human papillomavirus after activation with stabilized Poly-I:C.
abstract: Human papillomavirus (HPV)-mediated suppression of Langerhans cell (LC) function can lead to persistent infection and development of cervical intraepithelial neoplasia (CIN). Women with HPV-induced high-grade CIN2/3 have not mounted an effective immune response against HPV, yet it is unknown if LC-mediated T cell activation from such women is functionally impaired against HPV. We investigated the functional activation of in vitro generated LC and their ability to induce HPV16-specific T cells from CIN2/3 patients after exposure to HPV16 followed by treatment with stabilized Poly-I:C (s-Poly-I:C). LC from patients exposed to HPV16 demonstrated a lack of costimulatory molecule expression, inflammatory cytokine secretion, and chemokine-directed migration. Conversely, s-Poly-I:C caused significant phenotypic and functional activation of HPV16-exposed LC, which resulted in de novo generation of HPV16-specific CD8(+) T cells. Our results highlight that LC of women with a history of persistent HPV infection can present HPV antigens and are capable of inducing an adaptive T cell immune response when given the proper stimulus, suggesting that s-Poly-I:C compounds may be attractive immunomodulators for LC-mediated clearance of persistent HPV infection.
authors.affiliation: Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA; Department of Obstetrics & Gynecology, University of Southern California, Los Angeles, CA, USA. Electronic address: Diane.DaSilva@med.usc.edu.
authors.forename: Diane M
authors.initials: DM
authors.lastname: Da Silva
authors.affiliation: Department of Molecular Microbiology & Immunology, University of Southern California, Los Angeles, CA, USA.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Woodham
authors.affiliation: Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Skeate
authors.affiliation: Groningen International Program of Science in Medicine, University of Groningen, Groningen, The Netherlands.
authors.forename: Laurie K
authors.initials: LK
authors.lastname: Rijkee
authors.affiliation: Department of Molecular Microbiology & Immunology, University of Southern California, Los Angeles, CA, USA.
authors.forename: Julia R
authors.initials: JR
authors.lastname: Taylor
authors.affiliation: Department of Molecular Microbiology & Immunology, University of Southern California, Los Angeles, CA, USA.
authors.forename: Heike E
authors.initials: HE
authors.lastname: Brand
authors.affiliation: Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA; Department of Obstetrics & Gynecology, University of Southern California, Los Angeles, CA, USA.
authors.forename: Laila I
authors.initials: LI
authors.lastname: Muderspach
authors.affiliation: Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA; Department of Obstetrics & Gynecology, University of Southern California, Los Angeles, CA, USA.
authors.forename: Lynda D
authors.initials: LD
authors.lastname: Roman
authors.affiliation: Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA; Department of Obstetrics & Gynecology, University of Southern California, Los Angeles, CA, USA.
authors.forename: Annie A
authors.initials: AA
authors.lastname: Yessaian
authors.affiliation: Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA; Department of Obstetrics & Gynecology, University of Southern California, Los Angeles, CA, USA.
authors.forename: Huyen Q
authors.initials: HQ
authors.lastname: Pham
authors.affiliation: Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA; Department of Obstetrics & Gynecology, University of Southern California, Los Angeles, CA, USA.
authors.forename: Koji
authors.initials: K
authors.lastname: Matsuo
authors.affiliation: Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA; Department of Obstetrics & Gynecology, University of Southern California, Los Angeles, CA, USA.
authors.forename: Yvonne G
authors.initials: YG
authors.lastname: Lin
authors.affiliation: Akela Pharma Inc., Austin, TX, USA.
authors.forename: Greg M
authors.initials: GM
authors.lastname: McKee
authors.affiliation: Oncovir, Inc., Washington, D.C., USA.
authors.forename: Andres M
authors.initials: AM
authors.lastname: Salazar
authors.affiliation: Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA; Department of Obstetrics & Gynecology, University of Southern California, Los Angeles, CA, USA; Department of Molecular Microbiology & Immunology, University of Southern California, Los Angeles, CA, USA.
authors.forename: W Martin
authors.initials: WM
authors.lastname: Kast
mesh_terms: D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D004279:DNA, Viral / Q000276:immunology; D005260:Female; D052162:Human papillomavirus 16 / Q000276:immunology*; D006801:Humans; D007801:Langerhans Cells / Q000276:immunology* / Q000821:virology; D008213:Lymphocyte Activation / Q000276:immunology*; D008875:Middle Aged; D030361:Papillomavirus Infections / Q000276:immunology* / Q000821:virology; D011070:Poly I-C / Q000276:immunology*; D002583:Uterine Cervical Neoplasms / Q000276:immunology / Q000821:virology; D002578:Uterine Cervical Dysplasia / Q000276:immunology* / Q000821:virology*
chemical_list: D004279:DNA, Viral; D011070:Poly I-C
keywords: HPV16; Human papillomavirus; Immune evasion; Langerhans cells