Skip to main content
eScholarship
Open Access Publications from the University of California

UCLA

UCLA Electronic Theses and Dissertations bannerUCLA

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

Abstract

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.

Main Content
For improved accessibility of PDF content, download the file to your device.
Current View