{"doi":"10.1002/cncr.34607","title":"Spatial PD‐L1, immune‐cell microenvironment, and genomic copy‐number alteration patterns and drivers of invasive‐disease transition in prospective oral precancer cohort","abstract":"BACKGROUND: Studies of the immune landscape led to breakthrough trials of programmed death-1 (PD-1) inhibitors for recurrent/metastatic head and neck squamous cell carcinoma therapy. This study investigated the timing, influence of somatic copy-number alterations (SCNAs), and clinical implications of PD-L1 and immune-cell patterns in oral precancer (OPC). METHODS: ) and PD-L1 (membranous expression in cytokeratin-positive intraepithelial neoplastic cells and CD68) patterns by multiplex immunofluorescence in a 188-patient prospective OPC cohort, characterized by clinical, histologic, and SCNA risk factors and protocol-specified primary end point of invasive cancer. The authors used Wilcoxon rank-sum and Fisher exact tests, linear mixed effect models, mediation, and Cox regression and recursive-partitioning analyses. RESULTS: Epithelial, but not CD68 immune-cell, PD-L1 expression was detected in 28% of OPCs, correlated with immune-cell infiltration, 9p21.3 loss of heterozygosity (LOH), and inferior oral cancer-free survival (OCFS), notably in OPCs with low CD3/8 cell density, dysplasia, and/or 9p21.3 LOH. High CD3/8 cell density in dysplastic lesions predicted better OCFS and eliminated the excess risk associated with prior oral cancer and dysplasia. PD-L1 and CD3/8 patterns revealed inferior OCFS in PD-L1 high intrinsic induction and dysplastic immune-cold subgroups. CONCLUSION: This report provides spatial insight into the immune landscape and drivers of OPCs, and a publicly available immunogenomic data set for future precancer interrogation. The data suggest that 9p21.3 LOH triggers an immune-hot inflammatory phenotype; whereas increased 9p deletion size encompassing CD274 at 9p24.1 may contribute to CD3/8 and PD-L1 depletion during invasive transition. The inferior OCFS in PD-L1-high, immune-cold OPCs support the development of T-cell recruitment strategies.","journal":"Cancer","year":2023,"id":342051,"datarank":0.40620753016533157,"base_score":2.70805020110221,"endowment":2.70805020110221,"self_citation_contribution":0.40620753016533157,"citation_network_contribution":0.0,"self_endowment_contribution":0.40620753016533157,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9618,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":5677,"name":"Jianjun Zhang","orcid":"0000-0001-7872-3477","position":1,"is_corresponding":false},{"id":305657,"name":"Xin Zhao","orcid":"0000-0001-8502-0139","position":2,"is_corresponding":false},{"id":228169,"name":"Edwin R. Parra","orcid":"0000-0001-9068-1636","position":3,"is_corresponding":false},{"id":631344,"name":"Naohiro Uraoka","orcid":null,"position":4,"is_corresponding":false},{"id":288243,"name":"Heather Lin","orcid":"0000-0002-1779-7007","position":5,"is_corresponding":false},{"id":1078115,"name":"S. Andrew Peng","orcid":"0009-0005-7942-3384","position":6,"is_corresponding":false},{"id":14355,"name":"Adel K. El‐Naggar","orcid":"0000-0002-7175-9466","position":7,"is_corresponding":false},{"id":341260,"name":"Jaime Rodriguez‐Canales","orcid":"0000-0002-0885-2377","position":8,"is_corresponding":false},{"id":1078116,"name":"Jaejoon Song","orcid":"0000-0003-0671-2191","position":9,"is_corresponding":false},{"id":294098,"name":"Ann M. Gillenwater","orcid":"0000-0002-0935-0037","position":10,"is_corresponding":false},{"id":226199,"name":"Ignacio I. Wistuba","orcid":"0000-0003-3365-6340","position":11,"is_corresponding":false},{"id":24649,"name":"Jeffrey N. Myers","orcid":"0000-0003-4767-3408","position":12,"is_corresponding":false},{"id":999319,"name":"Kathryn A. Gold","orcid":"0000-0001-5165-4424","position":13,"is_corresponding":false},{"id":244404,"name":"Renata Ferrarotto","orcid":"0000-0002-3561-215X","position":14,"is_corresponding":false},{"id":72142,"name":"Patrick Hwu","orcid":"0000-0002-8293-1313","position":15,"is_corresponding":false},{"id":832844,"name":"Teresa Davoli","orcid":"0000-0003-4116-9745","position":16,"is_corresponding":false},{"id":37730,"name":"J. Jack Lee","orcid":"0000-0001-5469-9214","position":17,"is_corresponding":false},{"id":227923,"name":"John V. Heymach","orcid":"0000-0001-9068-8942","position":18,"is_corresponding":false},{"id":247615,"name":"Vassiliki A. Papadimitrakopoulou","orcid":"0000-0003-3172-1399","position":19,"is_corresponding":false},{"id":7922,"name":"Scott M. Lippman","orcid":"0000-0002-1643-4124","position":20,"is_corresponding":false},{"id":588979,"name":"William N. 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