title: Human papillomavirus 16 E6-specific CD45RA+ CCR7+ high avidity CD8+ T cells fail to control tumor growth despite interferon-gamma production in patients with cervical cancer.
abstract: We defined the nature of the cellular immune response in 5 women with human papillomavirus (HPV) 16+cervical carcinoma at a single time point when surgery was performed for treatment. To monitor the differences in T-cell recognition, 2 approaches of tetramer-guided technology were employed: (i) the in situ localization of major histocompatibility complex class I peptide complexes in the tumor lesions and (ii) the ex vivo sorting of HLA-A*0201-restricted and HPV16 E6-reactive T cells. CD8 T cells from the periphery (peripheral blood lymphocytes), the tumor (tumor-infiltrating lymphocytes), and T cells harvested from draining lymph nodes (T-LN) were analyzed. HPV16 E6 tetramer-sorted lymphocytes from the different anatomic sites recognized an HLA-A*0201-restricted E6 peptide irrespective of the type of antigen-presenting cells used for stimulation as determined by interferon-gamma production: autologous tumor cells, HLA-A*0201 surrogate antigen-presenting cells pulsed with the nominal peptide, and an HLA-A*0201-matched human dendritic cell line transgenic for HPV16 E6. Further analysis showed that the HPV16 E6-reactive CD8 T cells were of high avidity defined by blocking with an anti-CD8-alpha specific monoclonal antibody. We found that HPV16 E6-reactive T cells reside preferentially within the CD45RA+ CCR7+ T-cell subpopulation of tumor-infiltrating lymphocyte, peripheral blood lymphocyte, and T-LN in cervical cancer patients, suggesting that successful immune surveillance of HPV16+ tumor cells in cervical cancer patients is impaired. The CD45RA+/CCR7+ phenotype of HPV antigen-reactive T cells may serve as an indicator of dysfunctional T cells, despite effective interferon-gamma production in response to HPV antigens.
authors.affiliation: Cancer Center Research Laboratory, Thunder Bay Regional Health Sciences Center, Thunder Bay, Ontario, Canada.
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Zehbe
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Kaufmann
authors.forename: Markus
authors.initials: M
authors.lastname: Schmidt
authors.forename: Hanni
authors.initials: H
authors.lastname: Hohn
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Maeurer
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D015234:HLA-A Antigens / Q000276:immunology; D015789:HLA-A2 Antigen; D052162:Human papillomavirus 16; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis*; D017493:Leukocyte Common Antigens / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D009856:Oncogene Proteins, Viral / Q000276:immunology*; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000276:immunology*; D012097:Repressor Proteins / Q000276:immunology*; D002583:Uterine Cervical Neoplasms / Q000276:immunology* / Q000473:pathology / Q000821:virology
chemical_list: C515370:CCR7 protein, human; C068651:E6 protein, Human papillomavirus type 16; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D009856:Oncogene Proteins, Viral; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D012097:Repressor Proteins; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens