Myeloma Center, Winthrop P. Rockefeller Institute, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Department of Pathology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Cell Rep Med. 2023 Oct 17;4(10):101214. doi: 10.1016/j.xcrm.2023.101214. Epub 2023 Oct 3.
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.
多发性骨髓瘤（MM）的生长依赖于免疫耐受的骨髓微环境。在这里，我们发现肿瘤微环境细胞中丝氨酸/苏氨酸激酶 NIMA 相关激酶 2（NEK2）的缺失与 MM 生长抑制有关。缺乏 NEK2 会导致肿瘤相关巨噬细胞（TAMs）和抑制性 T 细胞减少。当用 MM 条件培养基刺激髓系祖细胞时，NEK2 的表达会促进功能性 TAMs 的产生。临床上，MM 细胞中 NEK2 的高表达与 CD8 T 效应记忆细胞的增加有关，而低 NEK2 与 IFN-γ 基因特征和激活的 T 细胞反应有关。抑制 NEK2 可上调 MM 细胞和髓样细胞中 PD-L1 的表达。在小鼠模型中，NEK2 抑制剂 INH154 与 PD-L1 阻断的联合应用可有效消除 MM 细胞并延长生存期。我们的研究结果为 NEK2 抑制可能克服肿瘤免疫逃逸并支持其进一步临床开发提供了有力证据。
