黑色素瘤中KEAP1的下调促进对免疫检查点阻断的抗性。
Downregulation of KEAP1 in melanoma promotes resistance to immune checkpoint blockade.
作者信息
Fox Douglas B, Ebright Richard Y, Hong Xin, Russell Hunter C, Guo Hongshan, LaSalle Thomas J, Wittner Ben S, Poux Nicolas, Vuille Joanna A, Toner Mehmet, Hacohen Nir, Boland Genevieve M, Sen Debattama R, Sullivan Ryan J, Maheswaran Shyamala, Haber Daniel A
机构信息
Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, 02114, USA.
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.
出版信息
NPJ Precis Oncol. 2023 Mar 2;7(1):25. doi: 10.1038/s41698-023-00362-3.
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.
免疫检查点阻断（ICB）已在黑色素瘤患者中显示出疗效，但许多患者反应不佳。通过对黑色素瘤患者来源的循环肿瘤细胞（CTC）进行单细胞RNA测序，并使用小鼠黑色素瘤模型进行功能表征，我们发现KEAP1/NRF2通路调节对ICB的敏感性，与肿瘤发生无关。NRF2负调节因子KEAP1在表达上存在内在差异，导致肿瘤异质性和亚克隆抗性。
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