Proliferation and Immune Response Gene Signatures Associated with Clinical Outcome to Immunotherapy and Targeted Therapy in Metastatic Cutaneous Malignant Melanoma

SIMPLE SUMMARY: The introduction of treatment with targeted therapies and immunotherapies has dramatically changed the outcome for patients with advanced cutaneous melanoma. However, only a subset of the patients has durable benefits from the treatment. This exploratory study aims to identify genes/gene signatures as predictive biomarkers for treatment outcomes in melanoma. Targeted transcriptomics and gene set enrichment analysis (GSEA) were applied in 28 melanoma samples collected before receiving treatment. Thirteen patients were treated with targeted therapy (TT) and 15 patients were treated with immune checkpoint inhibitors (ICI). Up-regulation of genes involved in immune processes was associated with a better outcome of TT. Down-regulation of proliferation and up-regulation of allograft rejection gene sets favored ICI patients. Further follow-up of the inverse relation between proliferation and allograft rejection gene signatures and relation to outcome is warranted. ABSTRACT: Targeted therapy (TT), together with immune checkpoint inhibitors (ICI), has significantly improved clinical outcomes for patients with advanced cutaneous malignant melanoma (CMM) during the last decade. However, the magnitude and the duration of response vary considerably. There is still a paucity of predictive biomarkers to identify patients who benefit most from treatment. To address this, we performed targeted transcriptomics of CMM tumors to identify biomarkers associated with clinical outcomes. Pre-treatment tumor samples from 28 patients with advanced CMM receiving TT (n = 13) or ICI (n = 15) were included in the study. Targeted RNA sequencing was performed using Ion AmpliSeq ™, followed by gene set enrichment analysis (GSEA) using MSigDB’s Hallmark Gene Set Collection to identify gene expression signatures correlating with treatment outcome. The GSEA demonstrated that up-regulation of allograft rejection genes, together with down-regulation of E2F and MYC targets as well as G2M checkpoint genes, significantly correlated with longer progression-free survival on ICI while IFNγ and inflammatory response genes were associated with a better clinical outcome on TT. In conclusion, we identify novel genes and their expression signatures as potential predictive biomarkers for TT and ICI in patients with metastatic CMM, paving the way for clinical use following larger validation studies.