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Downregulation of KEAP1 in melanoma promotes resistance to immune checkpoint blockade.

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.

SUBMITTER: Fox DB

PROVIDER: S-EPMC9981575 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Downregulation of KEAP1 in melanoma promotes resistance to immune checkpoint blockade.

Fox Douglas B DB Ebright Richard Y RY Hong Xin X Russell Hunter C HC Guo Hongshan H LaSalle Thomas J TJ Wittner Ben S BS Poux Nicolas N Vuille Joanna A JA Toner Mehmet M Hacohen Nir N Boland Genevieve M GM Sen Debattama R DR Sullivan Ryan J RJ Maheswaran Shyamala S Haber Daniel A DA

NPJ precision oncology 20230302 1

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 resistan ...[more]

PMID: 36864091

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