A novel TLR-9 agonist C792 inhibits plasmacytoid dendritic cell-induced myeloma cell growth and enhance cytotoxicity of bortezomib.
A novel TLR-9 agonist C792 inhibits plasmacytoid dendritic cell-induced myeloma cell growth and enhance cytotoxicity of bortezomib.
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一种新型的TLR-9激动剂C792抑制了浆细胞性树突状细胞诱导的骨髓瘤细胞生长并增强硼替佐米的细胞毒性。
作者：
我们先前在多发性骨髓瘤（MM）患者中的研究显示，骨髓（BM）中浆细胞样树突状细胞（pDC）数量增加，这既有助于免疫功能障碍，也促进肿瘤细胞生长，存活和耐药性。在这里，我们表明，一种新的Toll样受体（TLR-9）激动剂C792恢复MM患者pDC刺激T细胞增殖的能力。pDC与MM细胞的共培养诱导MM细胞生长;并且重要的是，C792抑制pDC诱导的MM细胞生长并触发凋亡。相反，单独用C792处理MM细胞或pDC不影响任一细胞类型的活力。与我们的体外数据一致，C792在人MM的鼠异种移植模型中抑制pDC诱导的MM细胞体内生长。机制研究表明，C792触发pDC成熟，增强干扰素-α和干扰素-λ分泌，并激活TLR-9/MyD 88信号传导轴。最后，C792增强硼替佐米、来那度胺、泊马度胺、SAHA或美法仑的抗MM活性。总的来说，我们的临床前研究为C792的临床试验提供了基础，无论是单独使用还是联合使用，都可以改善MM的免疫功能并克服耐药性。
Our prior study in multiple myeloma (MM) patients showed increased numbers of plasmacytoid dendritic cells (pDCs) in the bone marrow (BM) which both contribute to immune dysfunction as well as promote tumor cell growth, survival, and drug resistance. Here we show that a novel Toll-Like Receptor (TLR-9) agonist C792 restores the ability of MM patient-pDCs to stimulate T cell proliferation. Co-culture of pDCs with MM cells induces MM cell growth; and importantly, C792 inhibits pDC-induced MM cell growth and triggers apoptosis. In contrast, treatment of either MM cells or pDCs alone with C792 does not affect the viability of either cell type. In agreement with our in vitro data, C792 inhibits pDC-induced MM cell growth in vivo in a murine xenograft model of human MM. Mechanistic studies show that C792 triggers maturation of pDCs, enhances interferon-α and interferon-λ secretion, and activates TLR-9/MyD88 signaling axis. Finally, C792 enhances the anti-MM activity of bortezomib, lenalidomide, pomalidomide, SAHA, or melphalan. Collectively, our preclinical studies provide the basis for clinical trials of C792, either alone or in combination, to both improve immune function and overcome drug resistance in MM.
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影响因子：
32.4
作者：
Jego, G;Palucka, AK;Banchereau, J
通讯作者：
Banchereau, J
DOI：
10.1200/jco.2011.37.8919
发表时间：
2012-02-01
期刊：
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
影响因子：
--
作者：
Anderson KC
通讯作者：
Anderson KC
DOI：
10.1084/jem.185.6.1101
发表时间：
1997-03-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Grouard G;Rissoan MC;Filgueira L;Durand I;Banchereau J;Liu YJ
通讯作者：
Liu YJ
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：
3.1
作者：
Marshall, JD;Fearon, KL;Van Nest, G
通讯作者：
Van Nest, G