Page 37 - Strategies for non-invasive managementof high-grade cervical intraepithelial neoplasia - prognostic biomarkers and immunotherapy Margot Maria Koeneman

HPV infection and HPV induced lesions can both be cleared by a combination of the innate and
adaptive immune system. Controversy exists as to whether HPV infections are truly cleared or
just become latent as a result of the host immune response.(36) Whereas the innate immune 2 system acts mainly as an immune barrier to HPV infection, the cellular immune response of the
adaptive immune system is responsible for clearance of HPV-induced lesions of the cervix. The
humoral immune response to HPV infection is a slow and inconsistent process: only 50-70% of
those infected show seroconversion. The humoral immune response is believed to play no part in
lesions clearance, but seems to be protective against new infections.
The immune response to HPV and HPV induced lesions is a largely local process and relies on the individuals immune capacities, but is also influenced by characteristics of the virus and the infectious process: HPV is characterized by several immune evasion strategies and infection leads to active downregulation of immune responses.(34)
Several viral characteristics lead to immune evasion. Infection with HPV is a largely intraepithelial process with limited viraemia to activate the immune response. In addition, replication of HPV in the differentiating keratinocyte does not lead to cytolysis or cell death and an associated inflammatory reaction. This results in an impaired activation of both the innate and adaptive immune systems. Beside immune evasion, HPV also causes downregulation of immune responses at several stages. HPV inhibits interferon synthesis and signalling and dampens cytokine responses, down regulating both the innate and cellular immune response to infection. Furthermore, HPV seems to impair the normal function of several innate immune cells. Langerhans cells are not activated by the uptake of HPV capsids. Instead, dermal dendritic cells (DCs) may be the key players in the HPV recognition and initiation of the cellular immune response. NK cells show reduced cytotoxic activity and their cell receptor expression seems to be reduced in the presence of HPV. The combination of immune evasion and downregulation of the immune system enables HPV to reside in the host epithelium for a long time with limited immune response, leading to alteration of cellular processes as previously described with neoplastic progression as a result.
Immune response in persistent HPV infections
In most women, the immune response is able to clear HPV infection and induce regression of low grade CIN, in spite of the immune evasion and downregulation by HPV. Persistent HPV infection is present in a smaller subset of women, influenced by a combination of host and viral factors. These women are at risk for the development of high-grade CIN and cervical carcinoma. With neoplastic transformation and genomic instability, key mediators of the immune system such as cytokines, adhesion molecules, chemokines and their receptors are further deregulated. There is evidence for an impaired cell-mediated immune response in women with high-grade CIN. Activation of the adaptive immune system leads to differentiation of CD4+ lymphocytes into T-helper cells, which produce cytokines of two different profiles: Th-1 cytokines promote differentiation of CD8+ lymphocytes into CTLs, which stand at the base of the cell-mediated immune response to HPV infected cells. Th-2 cytokines induce antibody production, as part of the humoral immune response. In cervical neoplasia, increasing CIN grade is associated with a shift in
A review of prognostic biomarkers
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