Melanoma dedifferentiation induced by interferon-gamma epigenetic remodeling in response to anti-PD-1 therapy

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 (IFN?), through a global chromatin landscape changes leading to enrichment in specific hyperaccessible chromatin regions. The IFN?-induced dedifferentiation signature corresponded with improved outcomes in patients with melanoma, challenging the notion that neural crest dedifferentiation is entirely an adverse phenotype. Overall design: RNA sequencing of eight different human melanoma cell lines at baseline, following three days of TNF exposure, or following 2-5 weeks of IFNg exposure.