High NEK2 expression in myeloid progenitors suppresses T cell immunity in multiple myeloma.

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.

• Authors: Yan Cheng, Fumou Sun, Daisy V Alapat, Visanu Wanchai, David Mery, Wancheng Guo, Huojun Cao, Yuqi Zhu, Cody Ashby, Michael Anton Bauer, Intawat Nookaew, Eric R Siegel, Jun 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 Jr, Fenghuang Zhan
• Journal: Cell reports. Medicine (Cell Rep Med) Vol. 4 Issue 10 Pg. 101214 (10 17 2023) ISSN: 2666-3791 [Electronic] United States
• PMID: 37794587 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• B7-H1 Antigen

Topics

• Mice
• Animals
• Multiple Myeloma (genetics, metabolism)
• B7-H1 Antigen (genetics)
• T-Lymphocytes (metabolism)
• Cell Line, Tumor
• Myeloid Progenitor Cells (metabolism, pathology)
• Tumor Microenvironment