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.
Yeon Joo Kim, Katherine M. Sheu, Jennifer Tsoi, Gabriel Abril-Rodriguez, Egmidio Medina, Catherine S. Grasso, Davis Y. Torrejon, Ameya S. Champhekar, Kevin Litchfield, Charles Swanton, Daniel E. Speiser, Philip O. Scumpia, Alexander Hoffmann, Thomas G. Graeber, Cristina Puig-Saus, Antoni Ribas
Guidelines: The Editorial Board will only consider letters that we deem relevant and of interest to our readers. We will not post data that have not been subjected to peer review, nor will we post letters that are essentially a reiteration of another letter. We reserve the right to edit any letter for length, content, and clarity. Authors will be notified by e-mail if their letters were accepted. No appeals will be considered.
Specific requirements: All letters must be 400 words or fewer. You may enter the letter as plain text or HTML. The author's name and e-mail address are required, and will be posted with the letter. All possible conflicts of interest must be noted, even if they are not posted. If you wish to include a figure (keep in mind that non-peer-reviewed data will not be posted), please contact the editors directly at firstname.lastname@example.org.