Department of Medical Oncology, The LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Oncogene. 2020 Mar;39(13):2786-2796. doi: 10.1038/s41388-020-1172-0. Epub 2020 Feb 5.
Bone marrow plasmacytoid dendritic cells (pDCs) in patients with multiple myeloma (MM) promote tumor growth, survival, drug resistance, and immune suppression. Understanding the molecular signaling crosstalk among the tumor cells, pDCs and immune cells will identify novel therapeutic approaches to enhance anti-MM immunity. Using oligonucleotide arrays, we found that pDC-MM interactions induce metabolic enzyme Alpha-Enolase (ENO1) in both pDCs and MM cells. Analysis of MM patient gene expression profiling database showed that ENO1 expression inversely correlates with overall survival. Protein expression analysis showed that ENO1 is expressed in pDC and MM cells; and importantly, that pDC-MM coculture further increases ENO1 expression in both MM cells and pDCs. Using our coculture models of patient autologous pDC-T-NK-MM cells, we examined whether targeting ENO1 can enhance anti-MM immunity. Biochemical inhibition of ENO1 with ENO1 inhibitor (ENO1i) activates pDCs, as well as increases pDC-induced MM-specific CD8 CTL and NK cell activity against autologous tumor cells. Combination of ENO1i and anti-PD-L1 Ab or HDAC6i ACY-241 enhances autologous MM-specific CD8 CTL activity. Our preclinical data therefore provide the basis for novel immune-based therapeutic approaches targeting ENO1, alone or in combination with anti-PD-L1 Ab or ACY241, to restore anti-MM immunity, enhance MM cytotoxicity, and improve patient outcome.
骨髓浆细胞样树突状细胞 (pDC) 在多发性骨髓瘤 (MM) 患者中促进肿瘤生长、存活、耐药和免疫抑制。了解肿瘤细胞、pDC 和免疫细胞之间的分子信号串扰将确定增强抗 MM 免疫的新治疗方法。使用寡核苷酸阵列，我们发现 pDC-MM 相互作用诱导两种 pDC 和 MM 细胞中的代谢酶 Alpha-Enolase (ENO1)。对 MM 患者基因表达谱数据库的分析表明，ENO1 的表达与总生存期呈负相关。蛋白表达分析表明 ENO1 在 pDC 和 MM 细胞中表达；重要的是，pDC-MM 共培养进一步增加了两种 MM 细胞和 pDC 中的 ENO1 表达。使用我们的患者自体 pDC-T-NK-MM 细胞共培养模型，我们研究了靶向 ENO1 是否可以增强抗 MM 免疫。用 ENO1 抑制剂 (ENO1i) 抑制 ENO1 的生化作用可激活 pDC，并增加 pDC 诱导的 MM 特异性 CD8 CTL 和 NK 细胞对自体肿瘤细胞的活性。ENO1i 与抗 PD-L1 Ab 或 HDAC6i ACY-241 的联合使用增强了自体 MM 特异性 CD8 CTL 活性。因此，我们的临床前数据为针对 ENO1 的新型免疫治疗方法提供了基础，这些方法可单独或与抗 PD-L1 Ab 或 ACY241 联合使用，以恢复抗 MM 免疫、增强 MM 细胞毒性并改善患者预后。
