PD-L1 and FOXP3 expression in high-grade squamous intraepithelial lesions of the anogenital region

Host immunosurveillance is an important factor in the progression of high-grade squamous intraepithelial lesions (HSIL) into high-risk human papillomavirus (HR-HPV)-related squamous cell carcinoma. Immune escape by forkhead box protein P3 (FOXP3+) immunoregulatory T cells and the programmed death-ligand 1 (PD1/PD-L1) axis, mechanisms best described in the context of invasive neoplasms, may play a role in the evolution of pre-malignant lesions. This morphological study aimed to characterize the inflammatory response and expression of FOXP3 and PD-L1 in anal, vulvar, and penile HSILs and compare them with those in low-grade SILs co-infected with HR-HPV (LSIL_HR). The study group comprised 157 samples from 95 male and 55 female patients (median age = 35.5 years), including 122 HSILs and 35 LSILs_HR. Dense inflammatory infiltrates and high counts of FOXP3⁺ cells were significantly more frequent in patients with HSILs than in those with LSILs_HR (p = 0.04 and 0.02, respectively). HSILs also exhibited higher PD-L1 expression (p_adj < 0.01 and < 0.01 for the SP142 and 22C3 clones, respectively), based on the Poisson generalized linear model. In addition, concordant higher PD-L1 expression was observed in cases with a greater number of FOXP3+ cells (p < 0.05). Our findings indicate a putative role of transcriptionally active HR-HPV in evoking an inflammatory response and immune evasion in the early phases of carcinogenesis in a subset of non-cervical anogenital HSILs.