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:10.1038/s41698-023-00362-3

Downregulation of KEAP1 in melanoma promotes resistance to immune checkpoint blockade

NPJ Precis Oncol. 2023 Mar 2;7(1):25. doi: 10.1038/s41698-023-00362-3.

Authors

Douglas B Fox^#¹, Richard Y Ebright^#¹, Xin Hong^#^{1

2}, Hunter C Russell¹, Hongshan Guo^{1

3}, Thomas J LaSalle^{1

4}, Ben S Wittner¹, Nicolas Poux¹, Joanna A Vuille¹, Mehmet Toner^{5

6

7}, Nir Hacohen^{1

4}, Genevieve M Boland^{1

7}, Debattama R Sen^{1

8}, Ryan J Sullivan^{1

8}, Shyamala Maheswaran^{9

10}, Daniel A Haber^{11

12

13}

Affiliations

¹ Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, 02114, USA.
² Department of Biochemistry, School of Medicine and Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen, 518055, China.
³ Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China.
⁴ Broad Institute of Harvard and MIT, Cambridge, MA, 02139, USA.
⁵ Center for Engineering in Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
⁶ Shriners Hospitals for Children, Boston, MA, 02114, USA.
⁷ Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
⁸ Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
⁹ Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, 02114, USA. [email protected].
¹⁰ Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA. [email protected].
¹¹ Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, 02114, USA. [email protected].
¹² Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA. [email protected].
¹³ Howard Hughes Medical Institute, Bethesda, MD, 20815, USA. [email protected].

^# Contributed equally.

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.

Abstract

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