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Melanoma dedifferentiation induced by interferon-gamma epigenetic remodeling in response to anti-PD-1 therapy
- 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
Published Web Location
https://doi.org/10.1172/jci145859Abstract
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.
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