High NEK2 expression in myeloid progenitors suppresses T cell immunity in multiple myeloma PMID: 37794587

ADC Targets in Oncology

2026-04-10

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

Cell Rep Med. 2023 Sep 26:101214. doi: 10.1016/j.xcrm.2023.101214.

Yan Cheng ¹ , Fumou Sun ¹ , Daisy V Alapat ² , Visanu Wanchai ³ , David Mery ¹ , Wancheng Guo ¹ , Huojun Cao ⁴ , Yuqi Zhu ⁵ , Cody Ashby ⁶ , Michael Anton Bauer ⁶ , Intawat Nookaew ⁶ , Eric R Siegel ⁷ , Jun Ying ⁷ , Jin-Ran Chen ⁸ , Dongzheng Gai ¹ , Bailu Peng ¹ , Hongwei Xu ¹ , Clyde Bailey ¹ , Samer Al Hadidi ¹ , Carolina Schinke ¹ , Sharmilan Thanendrarajan ¹ , Maurizio Zangari ¹ , Marta Chesi ⁹ , P Leif Bergsagel ⁹ , Frits van Rhee ¹ , Siegfried Janz ¹⁰ , Guido Tricot ¹ , John D Shaughnessy Jr ¹ , Fenghuang Zhan ¹¹

Affiliations

1. Myeloma Center, Winthrop P. Rockefeller Institute, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
2. Department of Pathology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
3. Myeloma Center, Winthrop P. Rockefeller Institute, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; Department of Biomedical Informatics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
4. Iowa Institute for Oral Health Research, Division of Biostatistics and Computational Biology, Department of Endodontics, University of Iowa College of Dentistry, Iowa City, IA 52242, USA.
5. Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.
6. Department of Biomedical Informatics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
7. Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
8. Arkansas Children's Nutrition Center, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA.
9. Department of Hematology/Oncology, Mayo Clinic, Scottsdale, AZ 85259, USA.
10. Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
11. Myeloma Center, Winthrop P. Rockefeller Institute, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. Electronic address: [email protected].

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.

Keywords

NEK2; PD-L1; T cell immunity; bone marrow microenvironment; combination therapy; immune checkpoint blockade; interferon gamma gene signature; multiple myeloma; myeloid-derived suppressive cells; tumor-associated macrophages.