Department of Oncology, Hematology, Immunology, Rheumatology and Pulmology, University of Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany.
Department of Hematology and Oncology, University of Bonn, Bonn, Germany.
Cancer Immunol Immunother. 2012 Feb;61(2):193-202. doi: 10.1007/s00262-011-1096-1. Epub 2011 Aug 27.
Multiple approaches presently aim to combine targeted therapies using tyrosine kinase inhibitors with immunotherapy. Ex vivo-generated dendritic cells are frequently used in such strategies due to their unique ability to initiate primary T-cell immune responses. Besides governing tumor cell growth, many kinases targeted by tyrosine kinase inhibitors are involved in the development and function of dendritic cells and thus tyrosine kinase inhibitor therapy may cause immunoinhibitory side effects. We here report that exposure of developing human monocyte-derived dendritic cells to the BCR-ABL inhibitors imatinib, dasatinib, and nilotinib results in profound upregulation of the transmembrane glycoprotein osteoactivin that has recently been characterized as a negative regulator of T-cell activation. Thus, in line with osteoactivin upregulation, exposure to tyrosine kinase inhibitors resulted in significantly reduced stimulatory capacity of dendritic cells in mixed lymphocyte reactions that could be restored by the addition of blocking anti-osteoactivin antibody. Our data demonstrate that tyrosine kinase inhibitor-mediated inhibition of dendritic cell function is, at least in great part, mediated by upregulation of the immune inhibitory molecule osteoactivin.
目前有多种方法旨在将针对酪氨酸激酶的靶向治疗与免疫疗法相结合。由于其独特的启动原发性 T 细胞免疫反应的能力，体外生成的树突状细胞经常被用于此类策略。除了控制肿瘤细胞生长外，许多酪氨酸激酶抑制剂靶向的激酶也参与树突状细胞的发育和功能，因此酪氨酸激酶抑制剂治疗可能会引起免疫抑制的副作用。我们在这里报告，将发育中的人单核细胞来源的树突状细胞暴露于 BCR-ABL 抑制剂伊马替尼、达沙替尼和尼罗替尼中，会导致跨膜糖蛋白骨激活素的显著上调，该蛋白最近被表征为 T 细胞激活的负调节剂。因此，与骨激活素的上调一致，酪氨酸激酶抑制剂的暴露导致混合淋巴细胞反应中树突状细胞的刺激能力显著降低，而添加阻断抗骨激活素抗体可恢复其刺激能力。我们的数据表明，酪氨酸激酶抑制剂介导的树突状细胞功能抑制至少在很大程度上是通过免疫抑制分子骨激活素的上调来介导的。
