Blimp-1 is a prognostic indicator for progression of cervical intraepithelial neoplasia grade 2

Abstract

Background Progression of cervical intraepithelial neoplasia (CIN) to higher grade disease is associated with persistent human papillomavirus (HPV) infection and an absence of immune-mediated regression. However, the immune microenvironment that distinguishes progression from persistent or regressing lesions has not been well defined. Methods A total of 69 patients under the age of 25 with high-risk HPV-positive cytology and biopsy-confirmed p16-positive CIN2 were included in the study. Biopsies were stained using 20 antibodies to a range of immune markers. Based on a 2-year follow-up, samples were analysed in “progressor” (CIN3 +) or “persister/regressor” (CIN1, 2 or normal) groups. Results Progression was most strongly associated with Blimp-1 positive cell staining in the lesion (P = 0.0019) and with low numbers of infiltrating CD4 cells in the dermal region beneath the lesion (P = 0.0022). The presence of CD4, CD8 and T bet-positive cells in the dermal region most strongly correlated with CD11c cells in the persister/regressor but not the progressor group. Conclusion High numbers of Blimp-1 + cells in CIN2 lesions may predict progression to more severe disease. Measurement of Blimp-1 may have diagnostic utility for the determination of the need to treat women with cervical pre-cancer. Highlights CIN2 progression is associated with high numbers of Blimp-1 positive cells in the lesion. Detection of Blimp-1 in the lesion may have utility as a prognostic test to inform the need to treat CIN2.

The High-Risk Human Papillomavirus Type Influences the Tissue Microenvironment in Cervical Intraepithelial Neoplasia Grade 2

“…In HPV16/18 lesions, CD4+FoxP3+ cells were strongly correlated with HMGB1, whereas they were strongly correlated with Blimp1 expression in HPV ‘other’ lesions. Previously, we did not find any association between CD4+FoxP3+ cells and disease progression in CIN2+ lesions but did detect an increase in CD4-FoxP3+ cells in lesions that subsequently progressed to higher-grade disease [ 15 ]. Furthermore, we found that Blimp1 and HMGB1 expression in the lesion was associated with a higher likelihood of disease progression.…”

“…Consistent with these observations, commonly reported high-grade cervical disease associated cellular changes when compared with normal tissue include decreased CD4 and CD8 cells and increased IDO1-positive cells [ 34 ]. Changes associated with subsequent disease progression from CIN2 to CIN3 include decreased CD4+, T bet-positive, CD8+, and CD11c+ cells [ 15 ]. Overall, the reduced numbers of T cells in HPV16/18 compared with hr HPV ‘other’ tissues in this study may reflect inhibition of T cell proliferation in the local tissue microenvironment.…”

“…The patient cohort in this study are a subset of the participants of a larger observational management study, known as the ‘PRINCess’ trial, and have previously been reported [ 15 , 16 ]. For inclusion in the study reported here, women had to meet the following additional criteria: both hrHPV- and p16 INK4A -positive test results were required and CIN2 had been confirmed in the tissue at review by a second pathologist.…”

“…Biopsies of CIN2 lesions obtained from women that met the criteria outlined above were formalin-fixed, paraffin-embedded, and sectioned to 4 µm thick. The antigen retrieval, staining, and evaluation of the sections for the following markers has been previously described: CD4, Tbet, GATA3, interleukin (IL)-17, FoxP3, CD8, granzyme B, langerin, Fascin, CD11c, CD32, CD138, high mobility group box (HMGB)-1, B-lymphocyte-induced maturation protein (Blimp)-1, thymic stromal lymphopoietin (TSLP), IDO1, and programmed death-ligand-1 (PD-L1) [ 15 ].…”

Chemical Peeling Therapy Using Phenol for the Cervico-Vaginal Intraepithelial Neoplasia

“…The HPV genotype was determined using a PCR-based test (Genosearch-31; MBL, Nagoya, Japan) [16]. This test can detect 13 HR HPV types (16,18,31,33,35,39, 45, 51, 52, 56, 58, 59, and 68), probable high-risk (pHR) types (26, 53, 66, 70, 73, and 82), and low-risk (LR) types (6,11,42,44, 54, 55, 61, 62, 71, 84, 89, and 90). To identify additional pHR-HPV types, such as HPV34, 67, and 69, the uniplex PCR method [17] was used for some CIN or VaIN cases that tested negative with the aforementioned test.…”