Downregulation of KEAP1 in melanoma promotes resistance to immune checkpoint blockade

被引：0

作者：

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

机构：

[1] Massachusetts General Hospital Cancer Center and Harvard Medical School,Center for Engineering in Medicine

[2] Broad Institute of Harvard and MIT,Department of Surgery

[3] Massachusetts General Hospital and Harvard Medical School,Department of Medicine

[4] Shriners Hospitals for Children,Department of Biochemistry, School of Medicine and Key University Laboratory of Metabolism and Health of Guangdong

[5] Massachusetts General Hospital and Harvard Medical School,Liangzhu Laboratory

[6] Massachusetts General Hospital and Harvard Medical School,undefined

[7] Howard Hughes Medical Institute,undefined

[8] Southern University of Science and Technology,undefined

[9] Zhejiang University Medical Center,undefined

来源：

npj Precision Oncology | / 7卷

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摘要：

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.

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