PD-L1 Negative Status is Associated with Lower Mutation Burden, Differential Expression of Immune-Related Genes, and Worse Survival in Stage III Melanoma

Jason Madore, Dario Strbenac, Ricardo Vilain, Alexander M. Menzies, Jeen Y.H. Yang, John F. Thompson, Georgina V. Long, Graham J. Mann, Richard A. Scolyer*, James S. Wilmott

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

89 Citations (Scopus)

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. 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. 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. CD8Ahigh gene expression was associated with better melanomaspecific 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). 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.

Original languageEnglish
Pages (from-to)3915-3923
Number of pages9
JournalClinical Cancer Research
Volume22
Issue number15
DOIs
Publication statusPublished - 1 Aug 2016
Externally publishedYes

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