Muntinga Caroline L P, de Vos van Steenwijk Peggy J, Bekkers Ruud L M, van Esch Edith M G
Department of Gynecology and Obstetrics, Catharina Ziekenhuis Eindhoven, Michelangelolaan 2, 5623 EJ Eindhoven, The Netherlands.
GROW-School for Oncology and Reproduction, Maastricht University, Universiteitssingel 40, 6229 ER Maastricht, The Netherlands.
J Clin Med. 2022 Mar 5;11(5):1432. doi: 10.3390/jcm11051432.
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.
宫颈高级别鳞状上皮内病变（cHSIL）是由持续性高危型人乳头瘤病毒（hrHPV）感染所致。cHSIL的自然病程难以预测，这取决于多种病毒、临床和免疫因素。局部免疫在宫颈发育异常的发病机制、自然消退及进展过程中起关键作用；然而，其潜在机制尚不清楚。本综述的目的是概述在自然消退、持续存在以及对（免疫）治疗反应过程中免疫微环境的变化。在病变持续存在和进展过程中，与正常上皮相比，cHSIL的免疫微环境特征为上皮内CD3⁺、CD4⁺和CD8⁺ T细胞浸润及朗格汉斯细胞缺乏，而CD25⁺FoxP3⁺调节性T细胞（Tregs）和CD163⁺ M2巨噬细胞数量增加。自然消退的特征是Tregs数量少、上皮内CD8⁺ T细胞较多以及CD4⁺/CD25⁺ T细胞比例高。“热”免疫微环境似乎是cHSIL自然消退所必需的。此外，免疫疗法，如咪喹莫特和治疗性HPV疫苗接种，可能会增强已有的促炎免疫环境，促进病变消退。已有的免疫组成可能反映病变消退的潜力，从而为cHSIL免疫治疗提供一种可能的免疫生物标志物。
