Infiltrating T-cell markers in cervical carcinogenesis: a systematic review and meta-analysis

Abstract

Background: The host adaptive immune response helps determine which cervical HPV infections persist and progress to precancer and cancer, and systematic characterisation of T-cell infiltration would help inform key steps in cervical carcinogenesis.

Methods: A systematic review and meta-analysis were conducted of infiltrating T-cells in normal cervix, low-grade lesions, high-grade lesions, and invasive cancers including epithelial, stromal, and total tissue and the following markers: CD3, CD4, CD8, FoxP3, CD25, and the CD4:CD8 ratio. An additional qualitative review summarised longitudinal data on associations between infiltrating T-cells and cervical disease persistence, regression, progression, or prognosis.

Results: There were fewer CD3+, CD4+, and CD8+ cells in cervical lesions and more cells in cancers compared to normal epithelium. FoxP3 and CD25+ regulatory T-cell infiltration is high in persistent and precancerous lesions, and longitudinal data show improved outcomes with lower regulatory T-cell levels.

Conclusions: Successful immune evasion may reduce T-cell infiltration in HPV infected and precancerous epithelium, while invasive cancers are highly immunogenic, and regulatory T-cell infiltration increases with cervical disease progression. Understanding these factors may have prognostic value and could aid in novel treatment development and clinical guidelines, but published data are highly heterogeneous and leave important gaps to be filled by future studies.

Fig. 1. PRISMA diagram.

The initial and updated PubMed searches plus two additional records identified during the full-text review resulted in total of 4741 records reviewed. After title and abstract review, 3789 records were excluded leaving 952 for full-text review. The full-text review excluded an additional 716 records, leaving 236 records for potential abstraction. Of these, 72 were not abstracted for the reasons indicated and 164 were abstracted. After limiting to the T-cell markers of interest, 73 records remained for inclusion in the quantitative meta-analysis, longitudinal analysis, or qualitative summary of infiltrating T-cells in cervical tissue.

Fig. 2. Forest plots of T-cell infiltrate quantitative meta-analyses.

Forest plots of meta-analyses of infiltrating T-cell markers across cervical disease stages in total tissue, epithelium and stroma expressed as mean cells/mm² with 95% confidence intervals for the following markers: a CD3, b CD8, c CD4, d CD4:CD8 ratio, e FoxP3. There were no stromal normal FoxP3 reports, so this category is absent. CIN cervical intraepithelial neoplasia, LG low grade, HG high grade, MRAW raw (untransformed) mean, CI confidence interval.

Fig. 3. Conceptual model of infiltrating T-cells in cervical carcinogenesis.

Normal cervical tissue is infiltrated by T-cells and T-cell subsets that respond to infection as part of the adaptive immune response. When HPV infection becomes established and is not immunologically cleared, it evades immune detection with reduced cytotoxic (CD8+) and helper (CD4+) T-cell infiltration in both the epithelium and adjacent stromal tissue. It is unclear whether regulatory (CD25+, FoxP3+) T-cell infiltration is affected but some evidence suggests it begins to increase. When HPV infections persist and progress to cervical precancer, pro-immune T-cell subsets continue to be suppressed and regulatory (inhibitory T-cells) amplified. If the lesion progresses to invasive cancer, a highly immunogenic state is reached with high levels of pan, cytotoxic, and helper T-cells in the surrounding stroma and to some extent in the tumour itself. Regulatory T-cells may be relatively high, resulting in a worse prognosis, or low, resulting in a better prognosis.