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

Abstract

<div>Abstract<p><b>Purpose:</b> 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.</p><p><b>Experimental Design:</b> 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.</p><p><b>Results:</b> PD-L1–negative status was associated with lower nonsynonymous mutation (NSM) burden (<i>P</i> = 0.017) and worse melanoma-specific survival [HR = 0.28 (0.12–0.66), <i>P</i> = 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. <i>CD8A</i><sup>high</sup> gene expression was associated with better melanoma-specific survival [HR = 0.2 (0.05–0.87), <i>P</i> = 0.017] and restricted to PD-L1–positive stage III specimens. NF1 mutations were restricted to PD-L1–positive tumors (<i>P</i> = 0.041).</p><p><b>Conclusions:</b> 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. <i>Clin Cancer Res; 22(15); 3915–23. ©2016 AACR</i>.</p></div>