Distinct tumor microenvironment profiles characterize regressive versus progressive anal precancers

Oncogenesis of anal high-grade squamous intraepithelial lesions (HSIL) is highly variable. Therefore, all HSIL are ablated, leading to overtreatment and associated burden because not all lesions will progress to cancer. This exploratory study investigated differences in the tumor immune microenvironment between regressive and progressive HSIL in people living with HIV to enable a more tailored approach. Multiplex imaging mass cytometry showed more inflammation in HSIL that progressed to cancer and cancer samples, compared with HSIL that spontaneously regressed and controls. Densities of HLA-DR⁺ macrophage phenotypes were higher in regressive HSIL, while progressive HSIL showed a predominance of CD163⁺ and/or CD204⁺, HLA-DR^- macrophage phenotypes. Validation with immunofluorescence confirmed this phenotypical distribution. Moreover, HSIL lesions closest to progression, and HSIL in individuals with a low nadir CD4 count, showed more unfavorable macrophage profiles. These preliminary findings may support the development of biomarkers or immunotherapeutic targets, enabling more individualized treatment approaches for anal HSIL.