Abstract
Cervical high-grade squamous intraepithelial lesions (cHSILs) develop as a result of a persistent high-risk human papilloma virus (hrHPV) infection. The natural course of cHSIL is hard to predict, depending on a multitude of viral, clinical, and immunological factors. Local immunity is pivotal in the pathogenesis, spontaneous regression, and progression of cervical dysplasia; however, the underlying mechanisms are unknown. The aim of this review is to outline the changes in the immune microenvironment in spontaneous regression, persistence, and responses to (immuno)therapy. In lesion persistence and progression, the immune microenvironment of cHSIL is characterized by a lack of intraepithelial CD3+, CD4+, and CD8+ T cell infiltrates and Langerhans cells compared to the normal epithelium and by an increased number of CD25+FoxP3+ regulatory T cells (Tregs) and CD163+ M2 macrophages. Spontaneous regression is characterized by low numbers of Tregs, more intraepithelial CD8+ T cells, and a high CD4+/CD25+ T cell ratio. A ‘hot’ immune microenvironment appears to be essential for spontaneous regression of cHSIL. Moreover, immunotherapy, such as imiquimod and therapeutic HPV vaccination, may enhance a preexisting pro-inflammatory immune environment contributing to lesion regression. The preexisting immune composition may reflect the potential for lesion regression, leading to a possible immune biomarker for immunotherapy in cHSILs.
Highlights
Cervical cancer is preceded by premalignant stages known as cervical high-grade squamous intraepithelial lesions, referred to as cervical intraepithelial neoplasia (CIN) 2 and CIN 3, respectively, moderate and severe dysplasia [1,2]. cHSIL is the most commonly known premalignant neoplasia, affecting approximately 1–2% of all women worldwide each year [3]
Since the immune system plays an essential role in the natural history of Human papilloma virus (HPV)-related lesion development, persistence, and clearance, the aim of this narrative review is to provide an outline of the changes in the immune microenvironment of premalignant cervical lesions to provide insight into the importance of the local immune microenvironment in both cervical low-grade squamous intraepithelial lesions (cLSILs) and cHSIL for spontaneous regression andtherapy responses
We will first outline the role of professional antigen-presenting cells (APCs), which are crucial in adaptive anti-tumor responses since these connect the innate and adaptive immune system; we discuss macrophages in cervical neoplasia
Summary
Cervical cancer is preceded by premalignant stages known as cervical high-grade squamous intraepithelial lesions (cHSILs), referred to as cervical intraepithelial neoplasia (CIN) 2 and CIN 3, respectively, moderate and severe dysplasia [1,2]. cHSIL is the most commonly known premalignant neoplasia, affecting approximately 1–2% of all women worldwide each year [3]. CHSIL is the most commonly known premalignant neoplasia, affecting approximately 1–2% of all women worldwide each year [3] Development of these lesions is causally related to a persistent infection with high risk human papillomavirus (hrHPV) [4–7]. The immune system is known to play an important role in the protection against hrHPV infection and the regression and persistence of hrHPV-induced pathology, as reflected by the increased risk of HPV-related lesions and (pre)malignancies in immunosuppressed patients, e.g., HIV positive or transplant patients [8,33,34]. Since the immune system plays an essential role in the natural history of HPV-related lesion development, persistence, and clearance, the aim of this narrative review is to provide an outline of the changes in the immune microenvironment of premalignant cervical lesions to provide insight into the importance of the local immune microenvironment in both cLSIL and cHSIL for spontaneous regression and (immuno)therapy responses.
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