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Melanoma dedifferentiation induced by IFN-γ epigenetic remodeling in response to anti-PD-1 therapy.

  • Author(s): 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
  • et al.

Published Web Location

https://doi.org/10.1172/jci145859
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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