Kim, YJ; Sheu, KM; Tsoi, J; Abril-Rodriguez, G; Medina, E; Grasso, CS; Torrejon, DY; ... Ribas, A; + view all Kim, YJ; Sheu, KM; Tsoi, J; Abril-Rodriguez, G; Medina, E; Grasso, CS; Torrejon, DY; Champhekar, AS; Litchfield, K; Swanton, C; Speiser, DE; Scumpia, PO; Hoffmann, A; Graeber, TG; Puig-Saus, C; Ribas, A; - view fewer (2021) Melanoma dedifferentiation induced by IFN-γ epigenetic remodeling in response to anti–PD-1 therapy. The Journal of Clinical Investigation , 131 (12) , Article e145859. 10.1172/JCI145859.

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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.

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