title: Circulating human papillomavirus type 16 specific T-cells are associated with HLA Class I expression on tumor cells, but not related to the amount of viral oncogene transcripts.
abstract: Human papillomavirus (HPV) is a necessary factor in the pathogenesis of cervical cancer. Circulating HPV-specific T-cells responding to the E6 and E7 HPV proteins can be detected only in half of cervical cancer patients. Potential explanations for the absence of this response are lack of sufficient amounts of antigen to activate the immune response or local immune escape mechanisms. We studied the relationship between HPV 16 E6/E7 oncogene mRNA expression, human leukocyte antigen (HLA) expression on tumor cells and the presence of circulating E6- and E7-specific T-cell responses in cervical cancer patients. The amount of antigen was assessed by HPV E6/E7 mRNA expression levels measured by quantitative polymerase chain reaction. HLA Class I and Class II expression on tumor cells was analyzed by immunohistochemistry. A proliferative HPV-specific T-cell response was detected in 15/29 patients. The amount of HPV E6/E7 mRNA was not related to the presence of immune response. HLA Class I expression was downregulated in 19 patients and completely lost in 7 patients. HLA Class II expression was upregulated in 18 patients. HLA Class I expression on tumor cells showed a strong correlation with immunity (p = 0.001). Explicitly, all patients with complete HLA loss lacked HPV specific T-cell responses. The presence of circulating HPV-specific T-cells might reflect ongoing antitumor response that is sustained by CD8+ T-cells killing HLA Class I positive cancer cells. We hypothesize that HLA Class I expression status on tumor cells might as well influence the response to HPV E6/E7 directed immunotherapy.
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands. m.a.de_boer@lumc.nl
authors.forename: Marjon A
authors.initials: MA
authors.lastname: de Boer
authors.forename: Ekaterina S
authors.initials: ES
authors.lastname: Jordanova
authors.forename: Mariëtte I E
authors.initials: MI
authors.lastname: van Poelgeest
authors.forename: Brendy E
authors.initials: BE
authors.lastname: van den Akker
authors.forename: Sjoerd H
authors.initials: SH
authors.lastname: van der Burg
authors.forename: Gemma G
authors.initials: GG
authors.lastname: Kenter
authors.forename: Gert Jan
authors.initials: GJ
authors.lastname: Fleuren
mesh_terms: D000938:Antigen-Presenting Cells; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology*; D002277:Carcinoma / Q000276:immunology / Q000821:virology; D004279:DNA, Viral; D015536:Down-Regulation; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000032:analysis*; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D052162:Human papillomavirus 16 / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D009367:Neoplasm Staging; D009856:Oncogene Proteins, Viral / Q000032:analysis; D050725:Papillomavirus E7 Proteins; D030361:Papillomavirus Infections / Q000150:complications / Q000276:immunology* / Q000821:virology; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D012097:Repressor Proteins / Q000032:analysis; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000821:virology; D014158:Transcription, Genetic; D014412:Tumor Virus Infections / Q000150:complications / Q000276:immunology* / Q000821:virology; D015854:Up-Regulation; D002583:Uterine Cervical Neoplasms / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D019562:Viral Load
chemical_list: D004279:DNA, Viral; C068651:E6 protein, Human papillomavirus type 16; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16