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Melanoma dedifferentiation induced by interferon-gamma 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.

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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.

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