Identification and validation of ecto-5' nucleotidase as an immunotherapeutic target in multiple myeloma.
Identification and validation of ecto-5' nucleotidase as an immunotherapeutic target in multiple myeloma.
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DOI：
10.1038/s41408-022-00635-3
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发表时间：
2022-04-01
影响因子：
12.8
通讯作者：
Anderson KC
中科院分区：
文献类型：
--
作者：
Ray A;Song Y;Du T;Buon L;Tai YT;Chauhan D;Anderson KC
浆细胞样树突状细胞（pDC）与多发性骨髓瘤（MM）细胞、T或NK效应细胞在骨髓（BM）微环境中的相互作用诱导肿瘤细胞生长，以及抑制先天性和适应性免疫应答。定义pDC-MM相互作用触发的免疫抑制机制将使介入治疗的设计能够增强抗MM免疫力。在本研究中，我们表明pDC-MM相互作用诱导pDC和MM细胞中的代谢酶Ecto-5'核苷酸酶/CD 73。MM患者的基因表达数据库显示，CD 73水平与总生存率呈负相关。使用我们的pDC-MM共培养模型，我们发现用抗CD 73 Ab阻断CD 73：降低腺苷水平;激活MM患者pDC;触发针对自体患者MM细胞的细胞毒性T淋巴细胞（CTL）活性。抗CD 73抗体和免疫刺激剂TLR-7激动剂的组合增强自体MM特异性CD 8 + CTL活性。总之，我们的临床前数据表明，单独或与TLR-7激动剂组合的CD 73治疗靶向代表了恢复宿主抗MM免疫力的有前景的新策略。
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.
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影响因子：
25.7
作者：
Niu, Congrong;Li, Li;Fletcher, Simon P.
通讯作者：
Fletcher, Simon P.
细胞外嘌呤，嘌呤能受体和肿瘤生长。
影响因子：
8
作者：
Di Virgilio F;Adinolfi E
通讯作者：
Adinolfi E
影响因子：
50.3
作者：
Chauhan D;Singh AV;Brahmandam M;Carrasco R;Bandi M;Hideshima T;Bianchi G;Podar K;Tai YT;Mitsiades C;Raje N;Jaye DL;Kumar SK;Richardson P;Munshi N;Anderson KC
通讯作者：
Anderson KC
影响因子：
81.5
作者：
Kumar, Shaji K.;Rajkumar, Vincent;Anderson, Kenneth C.
通讯作者：
Anderson, Kenneth C.
影响因子：
11.4
作者：
Bae J;Hideshima T;Tai YT;Song Y;Richardson P;Raje N;Munshi NC;Anderson KC
通讯作者：
Anderson KC