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Melanoma Plasticity Induced by Pro-Inflammatory Cytokines in Response to Immunotherapy


Melanoma dedifferentiation has been reported as a state of cellular resistance to targeted therapy and immunotherapy as cancer cells revert to a more primitive cellular phenotype. In a patient with metastatic melanoma who received adoptive T-cell transfer therapy using T cells with receptors against the melanoma antigen recognized by T cells 1 (MART-1/ Melan-A), we observed dedifferentiation as a resistance mechanism after initial response. However, biopsies obtained from responding patients during anti-programmed cell death receptor 1 (PD-1) therapy had decreased expression of melanocytic markers and increased neural crest markers. 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 (IFNγ), through a global chromatin landscape change leading to enrichment in specific hyperaccessible chromatin regions. The IFNγ-induced dedifferentiation signature corresponded with improved outcomes in patients with melanoma, challenging the notion that neural crest dedifferentiation is an adverse phenotype.

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