PD-L1 Expression and Immune Escape in Melanoma Resistance to MAPK Inhibitors

<b>Purpose:</b> To examine the relationship between immune activity, PD-L1 expression, and tumor cell signaling, in metastatic melanomas prior to and during treatment with targeted MAPK inhibitors.<b>Experimental Design:</b> Thirty-eight tumors from 17 patients treated with BRAF inhibitor (<i>n</i> = 12) or combination BRAF/MEK inhibitors (<i>n</i> = 5) with known PD-L1 expression were analyzed. RNA expression arrays were performed on all pretreatment (PRE, <i>n</i> = 17), early during treatment (EDT, <i>n</i> = 8), and progression (PROG, <i>n</i> = 13) biopsies. HLA-A/HLA-DPB1 expression was assessed by IHC.<b>Results:</b> Gene set enrichment analysis (GSEA) of PRE, EDT, and PROG melanomas revealed that transcriptome signatures indicative of immune cell activation were strongly positively correlated with PD-L1 staining. In contrast, MAPK signaling and canonical Wnt/-β-catenin activity was negatively associated with PD-L1 melanoma expression. The expression of PD-L1 and immune activation signatures did not simply reflect the degree or type of immune cell infiltration, and was not sufficient for tumor response to MAPK inhibition.<b>Conclusions:</b> PD-L1 expression correlates with immune cells and immune activity signatures in melanoma, but is not sufficient for tumor response to MAPK inhibition, as many PRE and PROG melanomas displayed both PD-L1 positivity and immune activation signatures. This confirms that immune escape is common in MAPK inhibitor-treated tumors. This has important implications for the selection of second-line immunotherapy because analysis of mechanisms of immune escape will likely be required to identify patients likely to respond to such therapies. <i>Clin Cancer Res; 23(20); 6054-61. ©2017 AACR</i>.