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PD-L1 Negative Status is Associated with Lower Mutation Burden, Differential Expression of Immune-Related Genes, and Worse Survival in Stage III Melanoma.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2016 Aug 01; Vol. 22 (15), pp. 3915-23. Date of Electronic Publication: 2016 Mar 09. - Publication Year :
- 2016
-
Abstract
- Purpose: 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.<br />Experimental Design: 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.<br />Results: 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).<br />Conclusions: 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.<br /> (©2016 American Association for Cancer Research.)
- Subjects :
- B7-H1 Antigen metabolism
Biomarkers, Tumor
Gene Expression Profiling
High-Throughput Nucleotide Sequencing
Humans
Immunohistochemistry
Lymphocytes, Tumor-Infiltrating immunology
Lymphocytes, Tumor-Infiltrating metabolism
Melanoma mortality
Melanoma pathology
Neoplasm Metastasis
Neoplasm Staging
Prognosis
Survival Analysis
B7-H1 Antigen genetics
Gene Expression Regulation, Neoplastic
Melanoma genetics
Melanoma immunology
Mutation
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3265
- Volume :
- 22
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 26960397
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-15-1714