Importance of the Immune Microenvironment in the Spontaneous Regression of Cervical Squamous Intraepithelial Lesions (cSIL) and Implications for Immunotherapy

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.

Low-Grade Cervical Intraepithelial Neoplasia (CIN1) Evolution: Analysis of Opportunistic Preventive Vaccination Role

“…Literature data support the hypothesis that 80% of HR-HPV infections spontaneously clear within 18 months thanks to the host’s immune system [ 37 , 38 , 39 , 40 ]. The persistent infection (around 10%) develops an LSIL/CIN1 lesion, and its progression to HSIL/CIN2+ is sustained by a failure in the immune system.…”

“…The persistent infection (around 10%) develops an LSIL/CIN1 lesion, and its progression to HSIL/CIN2+ is sustained by a failure in the immune system. In fact, the pro-inflammatory HPV-specific immune response constitutes the base of the clearance of HPV in healthy women [ 40 ]. A previous study found that in low-grade CIN HPV-16-related, systematic T-cell response to HPV E2 protein was associated with lesion regression, whereas the T-cell response to HPV 16 E6 protein was associated with lesion progression.…”

“…A previous study found that in low-grade CIN HPV-16-related, systematic T-cell response to HPV E2 protein was associated with lesion regression, whereas the T-cell response to HPV 16 E6 protein was associated with lesion progression. Moreover, the cervical microenvironment (keratinocytes, immune cells, endothelial cells, pericytes, mesenchymal cells, and fibroblastic cells) plays a causal role in the progression or regression of HR-HPV-related lesions [ 40 ]. In addition, epithelial and stromal T cells CD4+ and CD8+ are low in LSIL/CIN1 compared with healthy subjects, showing that there is a reduction in HPV clearance in cases of CIN [ 41 , 42 , 43 , 44 ].…”

Alterations of Vaginal Microbiota and Chlamydia trachomatis as Crucial Co-Causative Factors in Cervical Cancer Genesis Procured by HPV

“…In CC, a compromised microenvironment is mainly a consequence of deconstructed constituent parts of the vaginal microenvironment [ 26 , 27 ]. The intrinsic problems recall the simultaneous presence of multiple factors, such as the high inflammatory state, the presence of SNPs on genes that regulate the expression of immunosuppressive cytokines and interleukins, and a persistent local dysbiosis; these, in turn, facilitate the long-term aggressiveness of the HPV and Chlamydia infection [ 19 , 28 ].…”

Changes in cervical cytokine profiles following focused ultrasound treatment for high‐risk human papillomavirus infection–related low‐grade cervical lesions

“…HPV infections are common in sexually active women, and most are transient infections that are cleared within months to 2 years after acquisition, without any clinical symptoms or signs 2 . However, persistent HR‐HPV infections develop in approximately 10% of infected women and are associated with the development of cervical premalignant lesions and their subsequent progression into invasive cervical cancer 3 . The host's immune system contains both innate and adaptive immune responses that are critical for successful defense against HPV infection.…”