Page 69 - Strategies for non-invasive managementof high-grade cervical intraepithelial neoplasia - prognostic biomarkers and immunotherapy Margot Maria Koeneman

Introduction
Cervical intraepithelial neoplasia (CIN) is caused by infection with human papilloma virus (HPV)
and is considered to be the precursor of cervical carcinoma. While high-grade CIN lesions can
progress to cervical carcinoma, approximately 20-40% of these lesions show spontaneous 3 regression.[1-4] Currently, the prognosis of individual lesions remains unpredictable, but the
quest for prognostic biomarkers is ongoing. Identification of biomarkers, predicting spontaneous
regression of high-grade CIN, may enable a more individualized treatment. Patients with a high
likelihood for spontaneous disease regression can then be selected for conservative management
by watchful waiting. A potential biomarker may be found in the Human Leucocyte Antigen (HLA) molecules. The HLA gene complex encodes the Major Histocompatibility Complex receptors on
the human cell-surface that enable antigen presentation to host immune cells. Clearance of CIN
lesions is an immune-mediated process, which is largely effected by a cellular immune reaction.
[5] As such, differences in HLA repertoire could influence the individual capacity for spontaneous
regression of the CIN lesion.
Epidemiological studies indeed show that differences in HLA repertoire influence the individual susceptibility for the development of CIN lesions and cervical carcinoma.[6-8] Moreover, several HLA alleles have been associated with regression or persistence of CIN lesions, which is the focus of the current study.[4, 9, 10] HLA-DRB1*13 has been associated with spontaneous regression and non-progression of low-grade CIN lesions, independently of HPV genotype.[9, 10] Only one publication studied the influence of HLA alleles on the spontaneous regression of high-grade CIN lesions and found that HLA-A*02:01 is associated with persistence of high-grade CIN, but only in non-HPV 16 positive lesions.[4] The influence of HLA-DRB1*13 on spontaneous regression in high- grade CIN lesions was not assessed in this study.
In summary, there is some evidence that HLA repertoire may influence spontaneous regression of high-grade CIN lesions. However, not all HLA genes have been studied in regard to spontaneous regression of these lesions and it remains unclear whether the protective effect of different HLA alleles on the development of cervical lesions is HPV specific.
We hypothesize that HLA alleles could function as prognostic biomarkers in high-grade CIN. The goal of our study is to assess the influence of HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1 on the spontaneous regression of high-grade CIN lesions. We also analyzed the association between these HLA alleles and the prevalence of HPV genotypes in high-grade CIN lesions, to assess a potential HPV-specific protective effect.
Materials and methods
The study has been performed and reported according to the STREGA guidelines for the reporting of genetic association studies and according to the PROBE criteria for biomarker research.[11, 12]
HLA as a prognostic biomarker
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