Cell reports. Medicine · 2023
High NEK2 expression in myeloid progenitors suppresses T cell immunity in multiple myeloma.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Cheng Yan, Sun Fumou, Alapat Daisy V, Wanchai Visanu, Mery David, Guo Wancheng, Cao Huojun, Zhu Yuqi, Ashby Cody, Bauer Michael Anton, Nookaew Intawat, Siegel Eric R, Ying Jun, Chen Jin-Ran, Gai Dongzheng, Peng Bailu, Xu Hongwei, Bailey Clyde, Al Hadidi Samer, Schinke Carolina, Thanendrarajan Sharmilan, Zangari Maurizio, Chesi Marta, Bergsagel P Leif, van Rhee Frits, Janz Siegfried, Tricot Guido, Shaughnessy John D, Zhan Fenghuang
Аннотация
Multiple myeloma (MM) growth is supported by an immune-tolerant bone marrow microenvironment. Here, we find that loss of Never in mitosis gene A (NIMA)-related kinase 2 (NEK2) in tumor microenvironmental cells is associated with MM growth suppression. The absence of NEK2 leads to both fewer tumor-associated macrophages (TAMs) and inhibitory T cells. NEK2 expression in myeloid progenitor cells promotes the generation of functional TAMs when stimulated with MM conditional medium. Clinically, high NEK2 expression in MM cells is associated with increased CD8+ T effector memory cells, while low NEK2 is associated with an IFN-γ gene signature and activated T cell response. Inhibition of NEK2 upregulates PD-L1 expression in MM cells and myeloid cells. In a mouse model, the combination of NEK2 inhibitor INH154 with PD-L1 blockade effectively eliminates MM cells and prolongs survival. Our results provide strong evidence that NEK2 inhibition may overcome tumor immune escape and support its further clinical development.