Melanoma dedifferentiation induced by IFN-γ epigenetic remodeling in response to anti–PD-1 therapy
Yeon Joo Kim, Katherine M. Sheu, Jennifer Tsoi, Gabriel Abril-Rodríguez, 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
Abstract
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.