PD-L1 negative status is associated with lower mutation burden, differential expression of immune-related genes, and worse survival in stage-III melanoma
A partir d'échantillons de ganglions lymphatiques prélevés sur 52 patients atteints d'un mélanome de stade III, cette étude évalue l'association entre l'expression de PD-L1 dans ces ganglions et la survie des patients
Purpose: Understanding why some melanomas test negative for PD-L1 by immunohistochemistry 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.
Methods: Immunohistochemistry for PD-L1 was assessed in 52 AJCC stage-III melanoma lymph node specimens and compared with specimen-matched comprehensive clinicopathological, genomic, and transcriptomic data.
Results: PD-L1 negative status was associated with lower non-synonymous 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. High CD8A 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.
Clinical Cancer Research , résumé, 2016