Page 15 - Strategies for non-invasive managementof high-grade cervical intraepithelial neoplasia - prognostic biomarkers and immunotherapy Margot Maria Koeneman

Two types of infection can be distinguished. In productive infections, the expression of viral E6 and 1 E7 is limited, leading to viral replication in normally differentiating cells of the cervical epithelium
and shedding of viral particles from the superficial layers. Productive infections may lead to minor
cellular reactions, which are histologically diagnosed as CIN1, or CIN 2 at the most. Transforming
infections, on the other hand, are characterized by a deregulation of viral gene expression in the basal cell layers, leading to a more abundant expression of the viral oncogenes E6 and E7.[3, 8] To date, it remains unclear whether a transforming infection is the result of a persisting and deregulated productive infection, or originates as a primary transforming infection.[9] In transforming infections, the expression of E6 and E7 induces uncontrolled cell proliferation and immortalization and makes the infected host cell susceptible to chromosomal instability. Viral integration in the host DNA and epigenetic changes further facilitate oncogenesis, by enhancing the expression of viral oncogenes and silencing of tumor-suppressor genes. Transforming infections are usually caused by high-risk HPV types and are histologically characterized by increased numbers of mitotic figures, actively replicating cells throughout the thickness of the epithelium and an increased nucleus to cytoplasm ratio. These cellular abnormalities are histologically diagnosed as high-grade CIN (CIN2-3). Persistent transforming infections can ultimately lead to cervical carcinoma, over a time frame of several years.[3, 8]
Natural history of CIN lesions
Not all high-grade CIN lesions would progress to cervical cancer if left untreated. It is estimated that approximately 30% of high-grade CIN lesions progress to cervical cancer, whereas spontaneous regression occurs in 20-40% of cases.[1, 10-13] Spontaneous regression of exclusively CIN2 lesions is even more common: regression rates of up to 74% have been described.[13-16] Regression of CIN lesions is induced by the host cellular immune system.[17, 18] Presentation of HPV antigens by antigen presenting cells triggers a T-cell response, comprising of cytotoxic T cells (CTLs), T helper cells (Th cells) and regulatory T cells (Tregs). An adequate host immune response leads to influx of CTLs, Th cells and macrophages into the HPV induced lesion, by which clearance is effected. However, in a subset of women, the immune response is insufficient for lesion clearance. This is in part due to the individual immune capacity, determined by genetic factors, acquired immunodeficiency and environmental factors such as smoking. Additionally, an insufficient immune response may be the result of immune evasion strategies of HPV and active downregulation of the immune response by the virus. Immune evasion results from the fact that HPV infection is a largely intraepithelial process with limited viremia to activate the immune system. Additionally, HPV replication does not lead to cytolysis and associated local inflammatory reactions. Active downregulation of the immune system is caused by impairment of APC functioning, inhibition of interferon synthesis and signaling, altered cytokine responses, downregulation of HLA expression on the cell surface and increased infiltration of Tregs. As such, the natural prognosis of CIN lesions is determined by a complex interaction between viral and host factors, with effects on a cellular and molecular level.
Introduction
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