title: Expression of CD56 by human papillomavirus E7-specific CD8+ cytotoxic T lymphocytes correlates with increased intracellular perforin expression and enhanced cytotoxicity against HLA-A2-matched cervical tumor cells.
abstract: Human papillomavirus (HPV) infection represents the most important risk factor for developing cervical cancer. In this study, we examine the potential of full-length E7-pulsed autologous dendritic cells (DCs) to induce antigen-specific CTL responses from the peripheral blood of healthy individuals against HLA-A2-matched HPV-16 and HPV-18-positive tumor target cells in vitro. We show that DCs pulsed with E7 oncoprotein can consistently stimulate antigen-specific CTL responses that recognize and lyse HPV-16 or HPV-18-positive naturally infected cervical cancer cell lines. HPV-negative, EBV-transformed lymphoblastoid cell lines (LCLs) sharing the HLA haplotype of the target tumor cells, as well as autologous donor LCLs, were not significantly killed by E7-specific CTLs. Cytotoxicity against HLA-A2-matched HPV-16 and HPV-18 tumor target cells could be significantly inhibited by anti-HLA class I and by anti-HLA-A2 monoclonal antibodies. CD8+ CTLs expressed variable levels of CD56 and showed a strongly polarized Type 1 cytokine profile. Sorting of the CD8+ T cells on the basis of CD56 expression demonstrated that the most highly cytotoxic CTLs were CD56+ and expressed higher levels of perforin and IFN-gamma, compared with the CD8+/CD56- population. Taken together, these data demonstrate that full-length, E7-pulsed DCs can consistently induce E7-specific CD8+ CTL responses in healthy individuals that are able to kill naturally HPV-16 and HPV-18-infected cancer cells, and that CD56 expression defines a subset of CD8+ CTLs with high cytolytic activity against tumor cells.
authors: Department of Obstetrics and Gynecology, University of Arkansas for Medical Sciences, Little Rock 72205-7199, USA.
authors: A D
authors: AD
authors: Santin
authors: P L
authors: PL
authors: Hermonat
authors: A
authors: A
authors: Ravaggi
authors: S
authors: S
authors: Bellone
authors: J J
authors: JJ
authors: Roman
authors: S
authors: S
authors: Jayaprabhu
authors: S
authors: S
authors: Pecorelli
authors: G P
authors: GP
authors: Parham
authors: M J
authors: MJ
authors: Cannon
mesh_terms: D019002:CD56 Antigen / Q000096:biosynthesis*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D002460:Cell Line; D004268:DNA-Binding Proteins; D003713:Dendritic Cells / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D015789:HLA-A2 Antigen / Q000378:metabolism*; D006801:Humans; D007167:Immunotherapy; D007371:Interferon-gamma / Q000096:biosynthesis*; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D050725:Papillomavirus E7 Proteins; D054353:Perforin; D010641:Phenotype; D052899:Pore Forming Cytotoxic Proteins; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism*; D013997:Time Factors; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000378:metabolism*
chemical_list: D019002:CD56 Antigen; D004268:DNA-Binding Proteins; C052633:E7 protein, Human papillomavirus type 18; D015789:HLA-A2 Antigen; D008562:Membrane Glycoproteins; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D052899:Pore Forming Cytotoxic Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D054353:Perforin; D007371:Interferon-gamma