Cervical cancer is induced by HPV in virtually all cases, but it is still unknown how these virus-positive tumors arise in the face of immunity. In this thesis we examined the role of different... Show moreCervical cancer is induced by HPV in virtually all cases, but it is still unknown how these virus-positive tumors arise in the face of immunity. In this thesis we examined the role of different arms of the adaptive immune response on cervical cancer. In previous studies, it was shown that cancer patients do have a detectable immune response against the HPV16 E6 and E7 antigens. However, in general this response was not associated with cytokine production. In the present study, the mechanism underlying this dysfunctional immune response was investigated by studying the presence, specificity and function of the local T-cell response in patients with HPV-induced cervical malignancies at different stages of disease. Low CD8/Treg ratio is a significant independent unfavorable prognostic factor in cervical cancer patients. Frequently, the tumor is also infiltrated with HPV-specific CD4+ and CD8+ T-cells which can potentially attack the tumor. The infiltrating T-cells also include HPV-specific regulatory T-cells which are able to suppress the reactivity of neighboring T-cells. Their presence may explain the failure of the immune system to control HPV-induced tumors. Show less
Immune surveillance is of utmost importance in preventing cervical carcinogenesis. Cytokines play a central role in directing and fine tuning the immune response. In cancer, cytokines can either be... Show moreImmune surveillance is of utmost importance in preventing cervical carcinogenesis. Cytokines play a central role in directing and fine tuning the immune response. In cancer, cytokines can either be involved in stimulating the anti-tumor immune response or in tumor growth and progression. The studies in this thesis concern molecular analyses of immune escape mechanisms besides HLA class I loss, such as loss of TNF_ expression and TGF-_ insensitivity in cervical cancer. We identified SerpinA1 and SerpinA3 as candidate genes involved in immune suppression and/or carcinogenesis in HLA positive tumors. With regard to TGF-_ insensitivity, we showed in an in vitro model that TGF-_ insensitivity in cervical cancer cells is associated with activation of pathways involved in proliferation like MAPK. Furthermore, we provide evidence that the TGF-_-Smad signaling pathway is functional in most cervical carcinomas and that inactivation of Smad2 or Smad4 genes as a cause for TGF-_ insensitivity is unlikely. Overall, the studies in this thesis show that loss of HLA class I, lack of TNF_ expression, resistance to TGF-_ growth inhibition, production of TGF-_ and SerpinA1 and/or SerpinA3 expression occur in cervical cancer cells and represent possible strategies to evade eradication by immune cells. Show less
To improve quality of cancer care treatment-related information is needed. This could be acquired by registries. Since January 1984, the Leiden University Medical Center (LUMC) collects... Show moreTo improve quality of cancer care treatment-related information is needed. This could be acquired by registries. Since January 1984, the Leiden University Medical Center (LUMC) collects prospectively more than 200 relevant clinical and pathological parameters of women with cervical cancer treated in the LUMC. The purpose of this thesis was to use the treatment-related information of this database, to get inside information and to become aware of possibilities for improvement in the current treatment procedures, in order to monitor the quality of treatment. Furthermore, when results of cancer treatment in terms of survival are good it is also important to focus on the sequelae of the treatment. The incidence of lymphedema, urinary and colorectal dysfunction has been reported with variable rates and sexual dysfunction after radical hysterectomy has been shown to occur in about 25% of the patients. Furthermore, a study assessed by vaginal plethysmography, showed that radical hysterectomy seems to be associated with a disturbed vaginal blood flow response during sexual arousal. The second purpose of this thesis was to monitor the sequelae of the treatment of women with a history of early stage cervical cancer in order to have measures in attempts to improve the quality of life. Show less
