High NEK2 expression in myeloid progenitors suppresses T cell immunity in multiple myeloma
Yan Cheng, Fumou Sun, Daisy Alapat, Visanu Wanchai, David E. Mery, Wancheng Guo, Huojun Cao, Yuqi Zhu, Cody Ashby, Michael Bauer, Intawat Nookaew, Eric R. Siegel, Binwu Ying, Jin‐Ran Chen, Dongzheng Gai, Bailu Peng, Hongwei Xu, Clyde Bailey, Samer Al Hadidi, Carolina Schinke, Sharmilan Thanendrarajan, Maurizio Zangari, Marta Chesi, P. Leif Bergsagel, Frits van Rhee, Siegfried Janz, Guido Tricot, John D. Shaughnessy, Fenghuang Zhan
Abstract
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.