文章：

鉴定与验证ecto-5'核苷酸酶作为多发性骨髓瘤的免疫治疗靶点

Identification and validation of ecto-5' nucleotidase as an immunotherapeutic target in multiple myeloma

原文发布日期：2022-04-01

DOI: 10.1038/s41408-022-00635-3

类型: Article

开放获取: 是

英文摘要：

Interaction of plasmacytoid dendritic cells (pDCs) with multiple myeloma (MM) cells, T- or NK-effector cells in the bone marrow (BM) microenvironment induces tumor cell growth, as well as inhibits innate and adaptive immune responses. Defining pDC-MM interaction-triggered immunosuppressive mechanism(s) will enable design of interventional therapies to augment anti-MM immunity. In the present study, we show that pDC-MM interactions induce metabolic enzyme Ecto-5' Nucleotidase/CD73 in both pDCs and MM cells. Gene expression database from MM patients showed that CD73 levels inversely correlate with overall survival. Using our pDC-MM coculture models, we found that blockade of CD73 with anti-CD73 Abs: decreases adenosine levels; activates MM patient pDCs; triggers cytotoxic T lymphocytes (CTL) activity against autologous patient MM cells. Combination of anti-CD73 Abs and an immune-stimulating agent TLR-7 agonist enhances autologous MM-specific CD8+ CTL activity. Taken together, our preclinical data suggest that the therapeutic targeting of CD73, alone or in combination with TLR-7 agonist, represents a promising novel strategy to restore host anti-MM immunity.
 

摘要翻译： 

浆细胞样树突状细胞（pDCs）在骨髓微环境中与多发性骨髓瘤细胞、T细胞或NK效应细胞相互作用，既能诱导肿瘤细胞生长，也会抑制先天性与适应性免疫反应。明确pDC-MM相互作用触发的免疫抑制机制，将有助于设计干预性疗法以增强抗MM免疫。本研究表明，pDC-MM相互作用会同时诱导pDCs和MM细胞表达代谢酶胞外-5'-核苷酸酶/CD73。多发性骨髓瘤患者的基因表达数据库显示，CD73水平与总体生存率呈负相关。通过pDC-MM共培养模型发现，使用抗CD73抗体阻断CD73可：降低腺苷水平；激活MM患者的pDCs；激发针对自体患者MM细胞的细胞毒性T淋巴细胞活性。抗CD73抗体与免疫刺激剂TLR-7激动剂联用，能进一步增强自体MM特异性CD8+ CTL活性。综上，临床前数据表明，靶向CD73的治疗方案（单独或联合TLR-7激动剂）是恢复宿主抗MM免疫力的新型潜力策略。

原文链接：

Identification and validation of ecto-5' nucleotidase as an immunotherapeutic target in multiple myeloma