Page 40 - Strategies for non-invasive managementof high-grade cervical intraepithelial neoplasia - prognostic biomarkers and immunotherapy Margot Maria Koeneman

Chapter 2
HPV16/18-negative-associated CIN.(44) One study was conducted in patients with histologically confirmed high-grade CIN. Trimble et al. found a decreased disease regression of non-HPV16 high-grade CIN in the presence of HLA*A201 in 100 patients. Disease regression was 14.3% for patients with non-HPV16 high-grade CIN who carried an HLA*A201 allele, compared to 42.3% in those without an HLA*A201 allele.(8) HLA*A201 is expressed by approximately half of the population. The authors hypothesise that the effect of HLA polymorphisms could be explained by either differences in efficiency of antigen presentation or an altered immune response, in which differences in generation of regulatory T cells and/or NK cells occur.
Lymphoproliferative response
Multiple components of the cell-mediated immune response have been studied as potential biomarkers in the natural history of CIN and several promising biomarkers have been identified. As part of a composite biomarker profile containing Rb, lesions size, CD4+ cells and condom use, Munk et al. established an association between lower numbers of CD4+ cells in the basal membrane and disease regression, in 162 women with histologically confirmed high-grade CIN during a median interval of 16 weeks.(6) Spontaneous regression occurred in 21% and was significantly increased in smaller lesions with increased Rb expression and a lower number of stromal CD4+ cells (regression in 53%). No correlation was found between disease regression and epithelial and stromal CD8+, CD138+ and CD25+ cells. The authors hypothesize that a lower number of stromal CD4+ cells, as a marker of T-helper cells, may reflect a more effective immune response: HPV immune modulation leads to a disturbed immune response with on-going activation of innate immune cells. Ovestad et al. retrospectively studied the local immune response in 55 patients with histologically confirmed CIN 2/3, which were followed for a mean of 12 weeks (5-34 weeks). (45) Assessment of helper T-cells, cytotoxic T-cells, regulatory T-cells and B-lymphocytes was done by quantification of CD4, CD8, CD 25, Foxp3 and CD 138. Regression occurred in 18%. After multivariate survival analysis, disease regression was independently predicted by higher stromal CD8+ cell numbers, higher CD4+/CD25+ cell ratio and lower stromal CD 138+ cell numbers, indicating a strong T-cell response. None of the HPV16-positive cases showed regression. Interestingly, HPV16 infection correlated with lower CD8+ cells and higher CD 25+ cells, indicating a potentially stronger immune modulatory effect of HPV16 than other types. Moreover, stromal CD25+ cells (possible regulatory T cells) were more common in persistent cases, indicating that the specific immune response may be suppressed in these cases. The association between local regulatory T cells and disease persistence or progression was also established by Kojima et al., in patients with low grade cytological abnormalities.(46) They evaluated 12 patients with regressing CIN 1/2 and 12 patients with persisting CIN 1/2 during 8-33 months and found significantly lower numbers of regulatory T cells in cytobrush material of CIN regressors as compared to non-regressors. Molling et al. studied the presence of systemic regulatory T cells (PMBCs) in 82 women with HPV16 positive low grade cytological abnormalities.(47) The frequency of regulatory T cells was significantly increased in women with persistent HPV16 infections, which may lead to an inefficient immune response and may contribute to subsequent progression to neoplasia. However, they found no differences in the presence of systemic regulatory T cells between patient who did and did not progress to CIN 3 during prospective follow-up. In conclusion, markers of local immune response have been shown to be associated with disease regression, although the
38