All-trans retinoic acid enhances murine dendritic cell migration to draining lymph nodes via the balance of matrix metalloproteinases and their inhibitors
All-trans retinoic acid enhances murine dendritic cell migration to draining lymph nodes via the balance of matrix metalloproteinases and their inhibitors
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DOI：
10.4049/jimmunol.179.7.4616
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发表时间：
2007-10-01
影响因子：
4.4
通讯作者：
Kobayashi, Masanobu
中科院分区：
文献类型：
--
作者：
Darmanin, Stephanie;Chen, Jian;Kobayashi, Masanobu
癌症通过操纵宿主的免疫系统来逃避免疫监视。树突状细胞（DC）在肿瘤组织中的隔离和随后的对其迁移的抑制是肿瘤诱导免疫抑制的几种机制之一。鉴于最近的研究结果显示，全反式维甲酸（ATRA）治疗后，癌症患者的肿瘤免疫反应的改善，我们试图确定在肿瘤免疫治疗的背景下，ATRA对DC的流动性的影响。我们的研究结果表明，ATRA，添加到分化的小鼠骨髓祖细胞，增强所产生的DC的侵袭能力。当在ATRA存在下分化时，在小鼠肿瘤内注射的未成熟DC在引流淋巴结中显示出增加的积累，但在非引流淋巴结和脾脏中没有。成熟DC通过基底膜基质向淋巴样趋化因子CCL 19和CCL 21的体外迁移在这些细胞中增强，尽管在存在基质金属蛋白酶（MMP）抑制剂的情况下不存在。ATRA引起MMP产生增加，同时其抑制剂（基质金属蛋白酶组织抑制剂或TIMP）产生减少。这影响DC中的MMP/TIMP平衡，特别是MMP-9和TIMP-1的平衡，有利于蛋白酶活性，从而允许增强的DC动员。总之，这项研究表明，ATRA是能够改善DC在肿瘤环境中的运输，并在临床上获得的令人鼓舞的结果，进一步支持的概念，ATRA可能是一个有价值的化学佐剂，目前的免疫策略癌症。
Cancers escape immune surveillance through the manipulation of the host's immune system. Sequestration of dendritic cells (DCs) within tumor tissues and the subsequent inhibition of their migration is one of the several mechanisms by which tumors induce immmosuppression. In view of recent findings depicting the improvement of tumor immune responses in cancer patients following all-trans retinoic acid (ATRA) treatment, we sought to identify the effects of ATRA on DC mobility in the context of tumor immunotherapy. Our results demonstrate that ATRA, added to differentiating murine bone marrow progenitor cells, enhances the invasive capacity of the resulting DCs. Immature DCs injected intratumorally in mice show increased accumulation in draining lymph nodes, but not in nondraining lymph nodes and spleens, when differentiated in the presence of ATRA. The in vitro migration of mature DCs through the basement membrane matrix toward the lymphoid chemokines CCL19 and CCL21 is enhanced in these cells, albeit not in the presence of a matrix metalloproteinase (MMP) inhibitor. An increase in MMP production with a simultaneous decrease in the production of their inhibitors (tissue inhibitors of matrix metalloproteinase or TIMPs) is provoked by ATRA. This affects the MMP/TIMP balance in DCs, in particular that of MMP-9 and TIMP-1, favoring protease activity and thus allowing for enhanced DC mobilization. In conclusion, this study demonstrates that ATRA is capable of improving DC trafficking in a tumor milieu and, in view of the encouraging results obtained in the clinic, further supports the notion that ATRA might be a valuable chemical adjuvant to current immunotherapeutic strategies for cancer.