Downregulation of KEAP1 in melanoma promotes resistance to immune checkpoint blockade
Douglas B. Fox, Richard Y. Ebright, Xin Hong, Hunter C. Russell, Hongshan Guo, Thomas J. LaSalle, Ben S. Wittner, Nicolas Poux, Joanna Vuille, Mehmet Toner, Nir Hacohen, Genevieve M. Boland, Debattama R. Sen, Ryan J. Sullivan, Shyamala Maheswaran, Daniel A. Haber
Abstract
Immune checkpoint blockade (ICB) has demonstrated efficacy in patients with melanoma, but many exhibit poor responses. Using single cell RNA sequencing of melanoma patient-derived circulating tumor cells (CTCs) and functional characterization using mouse melanoma models, we show that the KEAP1/NRF2 pathway modulates sensitivity to ICB, independently of tumorigenesis. The NRF2 negative regulator, KEAP1, shows intrinsic variation in expression, leading to tumor heterogeneity and subclonal resistance.