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Melanoma to rhabdomyosarcoma plasticity in the setting of immunotherapy
Andrew D Knight1,2, Emily J Robitschek3, Jia-Ren Lin4
1Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Abstract:
Acquired resistance to immune checkpoint inhibitors (ICIs) remains a significant challenge in the treatment of metastatic melanoma. Phenotypic plasticity, such as dedifferentiation and transdifferentiation, is an increasingly recognized mechanism for treatment resistance. We present a case of a man in his 70s with metastatic melanoma who experienced progression through sequential treatments including pembrolizumab in combination with the HDAC inhibitor entinostat, and ipilimumab. During treatment a histologically distinct pleomorphic rhabdomyosarcoma (RMS) emerged at metastatic sites. Longitudinally acquired tumor samples representing both phenotypes were analyzed using whole-exome sequencing (WES), RNA sequencing (RNA-seq) and high-plex tissue imaging (spatial proteomics). WES revealed driver mutations (e.g. NRAS, NF1) and loss-of-heterozygosity (LOH) shared between phenotypes indicating a common ancestral clone. Phylogenetic analysis demonstrated an early divergence of the phenotypes, with each later acquiring unique mutations. RNA-seq showed mutually exclusive expression of lineage-specific markers as well as epithelial-mesenchymal transition and myogenic gene set enrichment in the RMS samples. High-plex imaging identified distinct tumor microenvironments, with RMS lesions enriched in CD163+ macrophages.
Insights
Acquired resistance to immune checkpoint inhibitors (ICIs) in melanoma can involve phenotypic plasticity. A patient developed rhabdomyosarcoma (RMS) from melanoma, showing distinct genetic and molecular profiles despite a shared origin.
Area of Science:
- Oncology
- Cancer Biology
- Genetics
Background:
- Acquired resistance to immune checkpoint inhibitors (ICIs) is a major obstacle in metastatic melanoma treatment.
- Phenotypic plasticity, including dedifferentiation and transdifferentiation, is implicated in treatment resistance.
- Understanding resistance mechanisms is crucial for improving melanoma therapy.
Purpose of the Study:
- To investigate a rare case of acquired resistance to ICIs in metastatic melanoma.
- To analyze the genetic and molecular underpinnings of phenotypic switching from melanoma to rhabdomyosarcoma (RMS).
- To characterize the tumor microenvironment associated with treatment-emergent RMS.
Main Methods:
- Whole-exome sequencing (WES) and RNA sequencing (RNA-seq) of longitudinal tumor samples.
- High-plex tissue imaging (spatial proteomics) to analyze tumor microenvironments.
- Phylogenetic analysis to determine clonal evolution and divergence.
Main Results:
- Shared driver mutations (NRAS, NF1) and loss-of-heterozygosity (LOH) confirmed a common ancestral melanoma clone.
- Early divergence of phenotypes was observed, with distinct mutations acquired by each lineage.
- RNA-seq revealed mutually exclusive lineage markers and enrichment of epithelial-mesenchymal transition and myogenic gene sets in RMS.
- Spatial proteomics identified distinct tumor microenvironments, with RMS lesions showing enrichment of CD163+ macrophages.
Conclusions:
- Phenotypic plasticity can drive acquired resistance to ICIs in metastatic melanoma, leading to the emergence of distinct tumor types like RMS.
- Integrated genomic and proteomic analyses are essential for dissecting complex resistance mechanisms.
- Targeting specific tumor microenvironments may offer new therapeutic strategies for resistant melanoma.
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