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

J Clin Invest. 2021 Jun 15;131(12):e145859. doi: 10.1172/JCI145859.


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.

Trial registration: NCT01621490.

Keywords: Cancer immunotherapy; Cytokines; Oncology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor* / antagonists & inhibitors
  • Biomarkers, Tumor* / metabolism
  • Cell Dedifferentiation / drug effects*
  • Cell Line, Tumor
  • Epigenesis, Genetic / drug effects*
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Immune Checkpoint Inhibitors / pharmacology*
  • Interferon-gamma / metabolism*
  • Melanocytes / metabolism
  • Melanocytes / pathology
  • Melanoma* / drug therapy
  • Melanoma* / metabolism
  • Neoplasm Proteins* / antagonists & inhibitors
  • Neoplasm Proteins* / metabolism
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*


  • Biomarkers, Tumor
  • IFNG protein, human
  • Immune Checkpoint Inhibitors
  • Neoplasm Proteins
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Interferon-gamma

Associated data