Local immune response in the microenvironment of CIN2–3 with and without spontaneous regression

Abstract

Fifteen to thirty percent of cases with histologically confirmed CIN2-3 in cervical biopsies regress spontaneously (ie, show CIN1 or less in the follow-up cervical cone). The balance between immune-reactive cells from the host and high-risk human papillomavirus (hrHPV) genotypes may provide a biological explanation for this phenomenon. We retrospectively studied 55 cases of CIN2-3 in a cervical biopsy with subsequent cervical cone to assess whether hrHPV genotypes (by AMPLICOR and Linear Array tests) CD4, CD8, CD25, CD138 and Foxp3 cells (by quantitative immunohistochemistry) in the cervical biopsies can predict regression (defined as CIN1 or less in the follow-up cone biopsy). Eighteen percent of the CIN2-3 cases regressed (median biopsy-cervical cone time interval: 12.0 weeks, range: 5.0-34.1 weeks). HPV-16 correlated with low CD8 þ and high CD25 þ . None of the regressing CIN2-3 lesions contained HPV-16. The regressing CIN2-3 lesions had lower numbers of stromal CD138 þ and higher numbers of stromal CD8 þ cells; higher stromal and intra-epithelial ratios of CD4 þ /CD25 þ cells; higher ratios of CD8 þ /CD25 þ cells and lower ratios ofþ cells in the stroma. With multivariate survival analysis, stromal CD8 þ cell numbers, CD4 þ /CD25 þ cell ratios and CD138 þ cell numbers are found to be independent regression predictors. In conclusion, in non-HPV-16 CIN2-3 lesions, assessing stromal immune cells can be a useful prognostic indicator of regression or persistence.

Protein vaccination with HPV16 E7/Pep‐1 nanoparticles elicits a protective T‐helper cell‐mediated immune response

“…The most common high-risk types are the HPV-16 and HPV-18, respectively, associated with pre-cancers and cancers in various anogenital sites (e.g., cervix, vulva, vagina, and anus) (3)(4)(5)(6). The studies showed that HPV-specific T-cell responses induced by vaccines play an effective role in tumor regression (7)(8)(9)(10). The researchers indicated that therapeutic HPV vaccines have the potential to inhibit the tumor growth by targeting HPV oncoproteins (11).…”

Histopathologic follow‐up and human papillomavirus DNA test results in 290 patients with high–grade squamous intraepithelial lesion papanicolaou test results

“…8 Adding to the challenge of assessing noncorrelating histopathologic follow-up findings after HSIL Paps, many high-grade lesions spontaneously regress, especially in younger adults. [9][10][11][12][13][14] With the advent of Food and Drug Administration (FDA) -cleared routine Pap and high-risk (hr) human papillomavirus (HPV) DNA cotesting for women 30 and older, 15,16 an increasing number of women with HSIL Pap test results now also have hrHPV DNA test results available to further assess histopathologic follow-up findings and to potentially help inform follow-up management decisions. 17 Nonetheless, reports on the range of expected histopathologic follow-up outcomes for large numbers of patients with HSIL Pap results based on widely used FDA-cleared liquid-based cytology (LBC) and from-the-vial hrHPV DNA testing remain limited.…”

B-lymphocyte, Macrophage and Mast Cell Density in the Stroma Underlying HPV-Related Cervical Squamous Epithelial Lesions and their Relationship to Disease Severity: an Immunohistochemical Study

“…Concerning the predictive value of cell density for the outcome of LSIL, we found that none of the cell types assessed has such a potential, a finding in accordance to previous studies [58]; nevertheless, our results need to be corroborated using a larger sample. There are very few studies addressing the issue of lesion progression in relation to tissue immunity: in one study, regression of HSIL is related to lower numbers of stromal CD138+ plasma cells [59], whereas in another, macrophage density seems to increase in persistent or progressing LSIL in comparison to regressing ones [18]. On the other hand, assessment of systemic immunity has so far yielded controversial results: whereas one study shows that immune responses quantified by ELISPOT assays in peripheral blood do not predict regression of HSIL [60], another shows HPV16 E2-and E6-specific T lymphocyte responses (quantified by interferon-gamma ELISPOT) to correlate with progression or persistence of LSIL [61].…”

“…Data obtained in each analysis were processed automatically by the system. CLART ® HPV 2 kit allowed the detection of infection and coinfection of 35 different HPV genotypes, namely 6,11,16,18,26,31,33,35,39,40,42,43,44,45,51,52,53,54,56,58,59,61,62,66,68,70,71,72,73,81,82,83,84, 85 and 89 [24]. Diagnostic sensitivity and specificity of the CLART ® HPV 2 kit amount to 98.2% and 100% respectively, according to the manufacturer.…”