{"doi":"10.1016/j.modpat.2025.100918","title":"Expression of Programmed Death-Ligand 1 and Programmed Cell Death-1 Across the Anal Neoplasia Disease Continuum and Association With Survival in Anal Cancer","abstract":"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.","journal":"Modern Pathology","year":2025,"id":578493,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9531,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1488090,"name":"Cynthia Gasper","orcid":"0000-0002-5462-2337","position":1,"is_corresponding":false},{"id":445931,"name":"Ann Lazar","orcid":"0000-0002-6341-0360","position":2,"is_corresponding":false},{"id":108697,"name":"Kathryn M. Allaire","orcid":"0000-0003-2711-8415","position":3,"is_corresponding":false},{"id":265754,"name":"Teresa M. Darragh","orcid":"0000-0002-4382-9949","position":4,"is_corresponding":false},{"id":24099,"name":"Lawrence Fong","orcid":"0000-0002-6428-428X","position":5,"is_corresponding":false},{"id":265771,"name":"Joel M. Palefsky","orcid":"0000-0002-5097-3818","position":6,"is_corresponding":false},{"id":767545,"name":"Sona Chowdhury","orcid":null,"position":0,"is_corresponding":true}],"reference_count":44,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:58:20.638044Z","pmid":"41106476","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}