title: PD-L1 Negative Status is Associated with Lower Mutation Burden, Differential Expression of Immune-Related Genes, and Worse Survival in Stage III Melanoma.
abstract: Understanding why some melanomas test negative for PD-L1 by IHC may have implications for the application of anti-PD-1 therapies in melanoma management. This study sought to determine somatic mutation and gene expression patterns associated with tumor cell PD-L1 expression, or lack thereof, in stage III metastatic melanoma to better define therapeutically relevant patient subgroups.
  
  
  
  IHC for PD-L1 was assessed in 52 American Joint Committee on Cancer stage III melanoma lymph node specimens and compared with specimen-matched comprehensive clinicopathologic, genomic, and transcriptomic data.
  
  
  
  PD-L1-negative status was associated with lower nonsynonymous mutation (NSM) burden (P = 0.017) and worse melanoma-specific survival [HR = 0.28 (0.12-0.66), P = 0.002] in stage III melanoma. Gene set enrichment analysis identified an immune-related gene expression signature in PD-L1-positive tumors. There was a marked increase in cytotoxic T-cell and macrophage-specific genes in PD-L1-positive melanomas. CD8A(high) gene expression was associated with better melanoma-specific survival [HR = 0.2 (0.05-0.87), P = 0.017] and restricted to PD-L1-positive stage III specimens. NF1 mutations were restricted to PD-L1-positive tumors (P = 0.041).
  
  
  
  Tumor negative PD-L1 status in stage III melanoma lymph node metastasis is a marker of worse patient survival and is associated with a poor immune response gene signature. Lower NSM levels were associated with PD-L1-negative status suggesting differences in somatic mutation profiles are a determinant of PD-L1-associated antitumor immunity in stage III melanoma. Clin Cancer Res; 22(15); 3915-23. ©2016 AACR.
authors.affiliation: Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia. Sydney Medical School, The University of Sydney, Camperdown, New South Wales, Australia.
authors.forename: Jason
authors.initials: J
authors.lastname: Madore
authors.affiliation: School of Mathematics and Statistics, The University of Sydney Camperdown, New South Wales, Australia.
authors.forename: Dario
authors.initials: D
authors.lastname: Strbenac
authors.affiliation: Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia. Sydney Medical School, The University of Sydney, Camperdown, New South Wales, Australia. Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Vilain
authors.affiliation: Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia. Sydney Medical School, The University of Sydney, Camperdown, New South Wales, Australia. Department of Medical Oncology, Royal North Shore and Mater Hospitals, Sydney, New South Wales, Australia.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Menzies
authors.affiliation: School of Mathematics and Statistics, The University of Sydney Camperdown, New South Wales, Australia.
authors.forename: Jeen Y H
authors.initials: JY
authors.lastname: Yang
authors.affiliation: Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia. Sydney Medical School, The University of Sydney, Camperdown, New South Wales, Australia. Department of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
authors.forename: John F
authors.initials: JF
authors.lastname: Thompson
authors.affiliation: Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia. Sydney Medical School, The University of Sydney, Camperdown, New South Wales, Australia. Department of Medical Oncology, Royal North Shore and Mater Hospitals, Sydney, New South Wales, Australia.
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
authors.affiliation: Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia. Centre for Cancer Research, The University of Sydney at Westmead Millennium Institute, Westmead, New South Wales, Australia.
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Mann
authors.affiliation: Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia. Sydney Medical School, The University of Sydney, Camperdown, New South Wales, Australia. Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia. richard.scolyer@sswahs.nsw.gov.au.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Scolyer
authors.affiliation: Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia. Sydney Medical School, The University of Sydney, Camperdown, New South Wales, Australia.
authors.forename: James S
authors.initials: JS
authors.lastname: Wilmott
mesh_terms: D060890:B7-H1 Antigen / Q000235:genetics* / Q000378:metabolism; D014408:Biomarkers, Tumor; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D008545:Melanoma / Q000235:genetics* / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D009154:Mutation; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis; D016019:Survival Analysis
chemical_list: D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human