Abstract
BackgroundThe 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.MethodsA 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.ResultsThere 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.ConclusionsSuccessful 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.
Highlights
The host adaptive immune response helps determine which cervical human papillomaviruses (HPV) infections persist and progress to precancer and cancer, and systematic characterisation of T-cell infiltration would help inform key steps in cervical carcinogenesis
A total of 73 studies reported results of interest, including 61 studies with quantitative counts of T-cell markers reported in a manner suitable for meta-analysis (Table S1),[25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85 9] studies reporting CD25 levels which were qualitatively summarised, and 20 studies reporting longitudinal data
Results summary A formal meta-analysis was conducted of CD3, CD8, and CD4 counts at each of four disease levels in each of three tissue sections according to how results from each study were reported in the manuscripts (Figs. 2 and S1)
Summary
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. 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. The adaptive immune response is characterised by complex interactions between these T-cell types and many other components to clear infections without harming uninfected host tissue
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