Specific Aneuploidies Predict Immune Evasion and Poor Immunotherapy Response in Melanoma

Abstract

Melanoma is one of the leading cancer types treated with immune checkpoint blockade (ICB), yet a substantial proportion of patients fail to respond. While tumor mutational burden and PD-L1 expression are established ICB biomarkers, they leave large gaps in predictive accuracy. Somatic copy number alterations (SCNAs) are pervasive in melanoma but their role in shaping the tumor immune microenvironment (TME) and predicting immunotherapy outcomes has been insufficiently characterized. Here we present KaryoTME, an integrated computational framework that systematically links SCNAs to immune phenotypes using genomic, transcriptomic, and clinical data from over 15,000 patients. Applying this framework to skin melanoma (SKCM) within a pan-cancer context, we identify arm-level chromosome 1q gain and 9p loss as the most prominent SCNA events associated with an immune-cold tumor microenvironment. These alterations act through distinct mechanisms: 9p loss preferentially depletes NK and CD8+ T cells, whereas 1q gain is more strongly associated with reduced anti-tumor immune cell infiltration. At the focal level, regions 1q21 and 1q42 show the strongest immune-suppressive associations in melanoma. Applying the TUSON-Immune algorithm, we predict candidate Tumor immune Suppressor Genes (TiSG) and immune Oncogenes (iOG) within these chromosomal regions, revealing enrichment for pathways including IFN signaling, JAK/STAT pathway, and immune-suppressive cytokine secretion. Critically, 1q gain emerged as a strong and independent predictor of poor survival following anti-PD-1/PD-L1 therapy across two independent clinical cohorts: the MSK-IMPACT cohort (p = 0.018, N = 77) and a large real-world Caris Life Sciences dataset (HR = 1.2, p = 0.002, N = 1,167). Multivariate analysis confirmed that 1q gain predicts poor outcomes independently of CD8+ T-cell infiltration, B-cell infiltration, tumor mutational burden, and PD-L1 status. These findings establish chromosome 1q gain as a compelling biomarker of immunotherapy resistance in melanoma and highlight aneuploidies as underappreciated drivers of immune evasion in this disease.