Immunological responses in genital HPV infections and etiology of cervical cancer

Abstract: Cervical cancer is one of the most common forms of cancers in women. Every year approximately 450,000 women are diagnosed worldwide and 200,000 die. The sexually transmitted oncogenic human papillomavirus (HPV) types are established as the major etiological agents of cancer of the cervix. Eradication of cervical cancer by vaccination against HPV has therefore become a promising approach. However, there are more than 100 types of HPV and at least 10 of these are oncogenic. Knowledge of the quantitative importance of the different HPV types in carcinogenesis is needed. As only a small fraction of ever-infected women go on to develop cancer, the role of co-factors to HPV in cervical cancer also needs to be established for evaluation of different preventive actions and validation of intermediate endpoints for such interventions. Many co-factors have been suggested such as: HPV immune response determinants, other sexually transmitted and environmental agents as well as susceptibility genes. For development, implementation and evaluation of both prophylactic and therapeutic agents against HPV and cervical cancer, knowledge about HPV-immunity and how various co-factors influence HPV persistence and carcinogenesis is required. This thesis has investigated immunological responses and risk factors for control of HPV infection, for development of precursor stages of cancer and for invasive cervical cancer. Three studies are molecular epidemiological and longitudinal cohort studies of healthy women participating in biobank cohorts or clinical trials. The fourth study has analysed HPV immunity in a mouse model. In paper I, Nordic serumbanks were used to study risk factors for invasive cervical cancer in a nested case-control study. In total, 543 prospectively occurring cases and 2675 matched controls, were identified. The scrum samples were analysed for antibodies against HPV 6, 16 and 18, Chlamydia trachomatis and Herpes simplex virus type 2. The study found evidence of an etiological role of HPV 16 and 18 in the development of cervical cancer and suggests a cofactor role of Chlamydia trachomatis. Paper II investigated the ability of a DNA vaccine to induce immunity against the HPV 16 major capsid protein L1 in mice. Although, it is well known that HPV infection can be prevented with so called virus-like particles (VLPs), vaccination with DNA coding for these particles could have practical advantages compared to VLPs. Vaccination with a modified HPV16 L1 plasmid did induce both neutralising antibodies and cell-mediated immune responses against HPV 16 in mice. Paper III studied the concentrations of two cytokines (CXCL8 and IFN-gamma) in cervical secretions in a cohort study of HPV16 DNA positive women who on follow-up either had clearance or a persistent HPV 16 infection. CXCL8 is a chemokine that attracts various immune cells in inflammation and IFN-gamma is a cytokine that activates immune cells important for viral clearance. The women who cleared their infection had higher levels of both cytokines compared to women who were persistently infected. In paper IV, women participating in a population-based biobank cohort who either did or did not develop precursor stages of cervical cancer (CIN) on follow-up were screened for 14 killer immunoglobulin-like receptor (KIR) genes. KIRs are expressed on natural killer (NK ) cells and they can distinguish a normal cell from an abnormal. By doing so NK cells win spare healthy cells while killing the abnormal cell. More than 70 KIR genotypes were identified. One of which was associated with increased risk of CIN.