Melanoma dedifferentiation induced by IFN-γ epigenetic remodeling in response to anti-PD-1 therapy
Authors listYeon Joo Kim Katherine M Sheu Jennifer Tsoi Gabriel Abril-Rodriguez Egmidio Medina Catherine S Grasso Davis Y Torrejon Ameya S Champhekar Kevin Litchfield Charles Swanton Daniel E Speiser Philip O Scumpia Alexander Hoffmann Thomas G Graeber Cristina Puig-Saus Antoni Ribas
Melanoma dedifferentiation has been reported as 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 respond to anti-programmed cell death receptor 1 (PD-1) therapy 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 melanocytic differentiated underwent a process of neural crest dedifferentiation when continuously exposed to interferon gamma, through global chromatin landscape changes leading to enrichment in specific hyperaccessible chromatin regions. The interferon gamma-induced dedifferentiation signature corresponded with improved outcomes in patients with melanoma, challenging the notion that neural crest dedifferentiation is entirely an adverse phenotype.
Issue number 12