Cytokine expression & TGF-beta signaling in cervical cancer

Abstract

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 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.