Expression of Programmed Death-Ligand 1 and Programmed Cell Death-1 Across the Anal Neoplasia Disease Continuum and Association With Survival in Anal Cancer

High-risk human papillomavirus (HPV) is associated with anal high-grade intraepithelial lesion (aHSIL) and anal squamous cell carcinoma (aSCC). The prognostic significance of programmed death-ligand 1 (PD-L1)- expression in aSCC and its impact on overall survival is controversial. ASCC can evade immune surveillance by coopting the PD-L1/programmed cell death-1 (PD-1) immune checkpoint pathway, enhancing tumorigenesis. To assess the potential role of the PD-L1/PD-1 axis on tumor progression, we assessed PD-L1 and PD-1 expression on epithelial cells and immune cells by immunohistochemistry in nonlesional anal tissue (n = 22), aHSIL (n = 22), and aSCC (n = 52) from HIV-negative participants and people living with HIV. PD-L1 expression on epithelial cells was restricted to tumor cells with no expression in nonlesional and HSIL tissues, whereas PD-L1-positive immune cells were present across all 3 diagnostic stages. PD-1 expression was absent on epithelial cells, whereas PD-1-positive immune cells increased along the disease continuum from nonlesional to aSCC. The overall PD-L1 expression on epithelial cells and immune cells measured by the combined positive score (CPS) in aSCC and the aggregate PD-L1 score in nonlesional and HSIL showed a substantial increase from nonlesional to aHSIL to aSCC. In aSCC, PD-L1 expression on immune cells was more prominent than in tumor cells and correlated with increased immune cell infiltration and interferon gamma secretion. Ninety-two percent of aSCC exhibited an adaptive PD-L1 expression pattern characterized by PD-L1 expression on tumor cells, immune cells, or both. HIV status did not affect PD-L1/PD-1 expression in nonlesional, aHSIL, or aSCC. PD-L1 expression in treatment-naive aSCC was associated with improved overall survival. Those with CPS of 0 had a higher risk of death (hazard ratio, 15.2 [95% CI, 3.3-69; P = .0004; log-rank P < .0001]) compared with those with CPS >0. CPS may indicate the presence of immune activation and serve as a potential prognostic marker.