Causes, consequences and clinical significance of aneuploidy across melanoma subtypes.
Abstract Aneuploidy, the state of the cell in which the number of whole chromosomes or chromosome arms becomes imbalanced, has been recognized as playing a pivotal role in tumor evolution for over 100 years. In melanoma, the extent of aneuploidy, as well as the chromosomal regions that are affected differ across subtypes, indicative of distinct drivers of disease. Multiple studies have suggested a role for aneuploidy in diagnosis and prognosis of melanomas, as well as in the context of immunotherapy response. A number of key constituents of the cell cycle have been implicated in aneuploidy acquisition in melanoma, including [...]
Causes, consequences and clinical significance of aneuploidy across melanoma subtypes.
Abstract Aneuploidy, the state of the cell in which the number of whole chromosomes or chromosome arms becomes imbalanced, has been recognized as playing a pivotal role in tumor evolution for over 100 years. In melanoma, the extent of aneuploidy, as well as the chromosomal regions that are affected differ across subtypes, indicative of distinct drivers of disease. Multiple studies have suggested a role for aneuploidy in diagnosis and prognosis of melanomas, as well as in the context of immunotherapy response. A number of key constituents of the cell cycle have been implicated in aneuploidy acquisition in melanoma, including [...]
Obesity is associated with altered tumor metabolism in metastatic melanoma.
Abstract Purpose: Overweight/obese (OW/OB) patients with metastatic melanoma unexpectedly have improved outcomes with immune checkpoint inhibitors (ICI) and BRAF-targeted therapies. The mechanism(s) underlying this association remain unclear, thus we assessed the integrated molecular, metabolic, and immune profile of tumors, as well as gut microbiome features, for associations with patient body mass index (BMI). Experimental Design: Associations between BMI [normal (NL < 25) or OW/OB (BMI ≥ 25)] and tumor or microbiome characteristics were examined in specimens from 782 patients with metastatic melanoma across 7 cohorts. DNA associations were evaluated in The Cancer Genome Atlas cohort. RNA sequencing from 4 [...]
Hypoxia controls the glycome signature and galectin-8 – ligand axis to promote pro-tumorigenic properties of metastatic melanoma.
Abstract The prognosis for patients with metastatic melanoma (MM) involving distant organs is grim, and treatment resistance is potentiated by tumor-initiating cells (TIC) that thrive under hypoxia. MM cells, including TICs, express a unique glycome featuring i-linear poly-N-acetyllactosamines (poly-LacNAc) via loss of I-branching enzyme, β1,6 N-acetylglucosaminyltransferase 2 (GCNT2). Whether hypoxia instructs MM TIC development by modulating the glycome signature remains unknown. Here, we explored hypoxia-dependent alterations in MM glycome-associated genes and found that GCNT2 was downregulated and a galectin (Gal)-8 – ligand axis, involving both extracellular and cell-intrinsic Gal-8, was induced. Low GCNT2 levels correlated with poor patient outcome [...]
Comparative genomics provides etiological and biological insights into melanoma subtypes
Abstract Background: Metastasectomy for selected patients with melanoma was associated with improved survival in the era before effective systemic therapy. Emerging evidence shows that these benefits persist even in this era of BRAF-targeted therapy and immune checkpoint inhibitor immunotherapy. This study aimed to evaluate the outcomes of salvage metastasectomy after failure of systemic therapy. Methods: Stage 3 or 4 melanoma patients with extracranial disease progression after at least 4 weeks of systemic treatment between 2009 and 2020 were identified and categorized as resected to no evidence of disease (NED), non-progressive residual disease (NPRD), or progressive residual disease (PRD). Systemic [...]
Unveiling the tumor immune microenvironment of organ-specific melanoma metastatic sites.
Abstract Background: The liver is a known site of resistance to immunotherapy and the presence of liver metastases is associated with shorter progression-free and overall survival (OS) in melanoma, while lung metastases have been associated with a more favorable outcome. There are limited data available regarding the immune microenvironment at different anatomical sites of melanoma metastases. This study sought to characterize and compare the tumor immune microenvironment of liver, brain, lung, subcutaneous (subcut) as well as lymph node (LN) melanoma metastases. Methods: We analyzed OS in 1924 systemic treatment-naïve patients with AJCC (American Joint Committee on Cancer) stage IV [...]
Diet-driven microbial ecology underpins associations between cancer immunotherapy outcomes and the gut microbiome.
Abstract The gut microbiota shapes the response to immune checkpoint inhibitors (ICIs) in cancer, however dietary and geographic influences have not been well-studied in prospective trials. To address this, we prospectively profiled baseline gut (fecal) microbiota signatures and dietary patterns of 103 trial patients from Australia and the Netherlands treated with neoadjuvant ICIs for high risk resectable metastatic melanoma and performed an integrated analysis with data from 115 patients with melanoma treated with ICIs in the United States. We observed geographically distinct microbial signatures of response and immune-related adverse events (irAEs). Overall, response rates were higher in Ruminococcaceae-dominated microbiomes [...]
High-Dimensional Single-Cell Transcriptomics in Melanoma and Cancer Immunotherapy
Abstract Recent advances in single-cell transcriptomics have greatly improved knowledge of complex transcriptional programs, rapidly expanding our knowledge of cellular phenotypes and functions within the tumour microenvironment and immune system. Several new single-cell technologies have been developed over recent years that have enabled expanded understanding of the mechanistic cells and biological pathways targeted by immunotherapies such as immune checkpoint inhibitors, which are now routinely used in patient management with high-risk early-stage or advanced melanoma. These technologies have method-specific strengths, weaknesses and capabilities which need to be considered when utilising them to answer translational research questions. Here, we provide guidance [...]
Combined presentation and immunogenicity analysis reveals a recurrent RAS.Q61K neoantigen in melanoma.
Abstract Neoantigens are now recognized drivers of the antitumor immune response. Recurrent neoantigens, shared among groups of patients, have thus become increasingly coveted therapeutic targets. Here, we report on the data-driven identification of a robustly presented, immunogenic neoantigen that is derived from the combination of HLA-A*01:01 and RAS.Q61K. Analysis of large patient cohorts indicated that this combination applies to 3% of patients with melanoma. Using HLA peptidomics, we were able to demonstrate robust endogenous presentation of the neoantigen in 10 tumor samples. We detected specific reactivity to the mutated peptide within tumor-infiltrating lymphocytes (TILs) from 2 unrelated patients, thus [...]
Clinical and Molecular Heterogeneity in Patients with Innate Resistance to Anti-PD-1 +/- Anti-CTLA-4 Immunotherapy in Metastatic Melanoma Reveals Distinct Therapeutic Targets.
Abstract While immune checkpoint inhibitors targeting the CTLA-4 and PD-1 receptors have significantly improved outcomes of many patients with metastatic melanoma, there remains a group of patients who demonstrate no benefit. In this study, we sought to characterise patients who do not respond to anti-PD-1-based therapies based on their clinical, genetic and immune profiles. Forty patients with metastatic melanoma who did not respond to anti-PD-1 +/− anti-CTLA-4 treatment were identified. Targeted RNA sequencing (n = 37) was performed on pretreatment formalin-fixed paraffin-embedded (FFPE) melanoma specimens. Patients clustered into two groups based on the expression profiles of 26 differentially expressed genes: [...]