Melanoma dedifferentiation induced by IFN-γ epigenetic remodeling in response to anti-PD-1 therapy
| Autor: | Kim, Yeon Joo, Sheu, Katherine M, Tsoi, Jennifer, Abril-Rodriguez, Gabriel, Medina, Egmidio, Grasso, Catherine S, Torrejon, Davis Y, Champhekar, Ameya S, Litchfield, Kevin, Swanton, Charles, Speiser, Daniel E, Scumpia, Philip O, Hoffmann, Alexander, Graeber, Thomas G, Puig-Saus, Cristina, Ribas, Antoni |
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| Rok vydání: | 2021 |
| Předmět: |
Neoplastic
Tumor Programmed Cell Death 1 Receptor Human Genome Immunology Cancer immunotherapy Cell Dedifferentiation Medical and Health Sciences Cell Line Neoplasm Proteins Interferon-gamma Genetic Gene Expression Regulation Oncology Genetics Melanocytes Humans Cytokines Melanoma Immune Checkpoint Inhibitors Biomarkers Epigenesis Cancer |
| Zdroj: | The Journal of clinical investigation, vol 131, iss 12 |
| Popis: | Melanoma dedifferentiation has been reported to be a state of cellular resistance to targeted therapies and immunotherapies as cancer cells revert to a more primitive cellular phenotype. Here, we show that, counterintuitively, the biopsies of patient tumors that responded to anti-programmed cell death 1 (anti-PD-1) therapy had decreased expression of melanocytic markers and increased neural crest markers, suggesting treatment-induced dedifferentiation. When modeling the effects in vitro, we documented that melanoma cell lines that were originally differentiated underwent a process of neural crest dedifferentiation when continuously exposed to IFN-γ, through global chromatin landscape changes that led to enrichment in specific hyperaccessible chromatin regions. The IFN-γ-induced dedifferentiation signature corresponded with improved outcomes in patients with melanoma, challenging the notion that neural crest dedifferentiation is entirely an adverse phenotype. |
| Databáze: | OpenAIRE |
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