T-cell responses to human papillomavirus in men with anal high-grade squamous intraepithelial lesions

Abstract

Anal cancer incidence in men who have sex with men (MSM) infected with human immunodeficiency virus (HIV) is three times greater than cervical cancer incidence was before Papanicolaou screening. Analogous to cervical cancer, most anal cancers are caused by human papilloma virus type 16 (HPV16) and is preceded by a precancerous stage termed high-grade squamous intraepithelial lesion (HSIL). Unlike cervical cancer, the natural history of anal HSIL is poorly understood, and there is little evidence to inform prevention guidelines.

In a retrospective audit of 574 men (73% HIV-infected) attending our anal cancer screening clinic, annual progression rate to HSIL was 7.4%, and for HSIL to cancer was 1.2%. This was the first study to quantify a spontaneous regression rate from HSIL, which was common at 23.5% per year.

To further understand the role of the cellular immune response in anal HSIL spontaneous regression, two assays were developed to measure systemic HPV16-specific T-cell responses and applied to a cross-sectional substudy of the Study of the Prevention of ANal Cancer (SPANC), a prospective, natural history study of anal cancer precursors and HPV in MSM ≥35 years. CD4+ T-cell responses to the HPV16 oncogenic protein E6 were detected in 80 (N=134, 60%) men. These responses may be associated with recent HSIL regression – five of six (83%) regressors had these responses compared to seven of 20 (35%) non-regressors (P exact=0.065).

T-cell immune responses in the anal mucosa were also studied in the above 26 men with HSIL at study entry. 24 (55%) biopsies had stromal lymphoid aggregates. Using whole slide imaging (600x) and two-colour immunofluorescent staining, CD4+ and CD8+ T-cell densities were measured. Lymphoid aggregates were CD4+ T-cell enriched (2.8-fold higher in density, P<0.01) compared to CD8+ T-cells (1.7-fold higher, P=0.08). Biopsies with HSIL diagnosis and having anal HPV16 detected were associated with higher total T-cell density.

In summary, anal HSIL spontaneous regression is common. A T-cell mediated mechanism for regression is plausible. This should be taken into account when developing screening and treatment strategies for anal HSIL.