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Figure S4 from PD-L1 Negative Status is Associated with Lower Mutation Burden, Differential Expression of Immune-Related Genes, and Worse Survival in Stage III Melanoma

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posted on 2023-03-31, 18:29 authored by 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

Melanoma-specific survival Validation Set. PD-L1 negative/CD8A low was associated with worse survival versus PD-L1 positive/CD8A low or PD-L1 positive/CD8A high (p = 0.014; log rank). An outlier case of PD-L1 negative/CD8A high was also observed in the validation set.


Melanoma Institute Australia

National Health and Medical Research Council



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 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).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.