npj Precision Oncology (Mar 2023)

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 A. Vuille,
  • Mehmet Toner,
  • Nir Hacohen,
  • Genevieve M. Boland,
  • Debattama R. Sen,
  • Ryan J. Sullivan,
  • Shyamala Maheswaran,
  • Daniel A. Haber

DOI
https://doi.org/10.1038/s41698-023-00362-3
Journal volume & issue
Vol. 7, no. 1
pp. 1 – 7

Abstract

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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.