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.
Dynavax Technologies, Berkeley, CA, USA.
Leukemia. 2014 Aug;28(8):1716-24. doi: 10.1038/leu.2014.46. Epub 2014 Jan 30.
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. Coculture 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, 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.
我们之前在多发性骨髓瘤（MM）患者中的研究表明，骨髓（BM）中的浆细胞样树突状细胞（pDC）数量增加，这既导致免疫功能障碍，又促进肿瘤细胞生长、存活和耐药性。在这里，我们表明一种新型 Toll 样受体（TLR-9）激动剂 C792 恢复了 MM 患者 pDC 刺激 T 细胞增殖的能力。pDC 与 MM 细胞共培养可诱导 MM 细胞生长；重要的是，C792 抑制 pDC 诱导的 MM 细胞生长并触发细胞凋亡。相比之下，单独用 C792 处理 MM 细胞或 pDC 均不会影响这两种细胞类型的活力。与我们的体外数据一致，C792 在人 MM 的小鼠异种移植模型中抑制 pDC 诱导的 MM 细胞生长。机制研究表明，C792 触发 pDC 的成熟，增强干扰素-α和干扰素-λ的分泌，并激活 TLR-9/MyD88 信号通路。最后，C792 增强硼替佐米、来那度胺、SAHA 或美法仑对 MM 的抗 MM 活性。总之，我们的临床前研究为 C792 的临床试验提供了依据，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。
