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* Division of Cancer-Related Genes,
Division of Cancer Biology, Institute for Genetic Medicine,
Department of Gastroenterology and Hematology,
Department of Nuclear Medicine,
¶ Department of Health Sciences,
|| Department of Molecular Imaging, Hokkaido University Graduate School of Medicine, Hokkaido University; and
# Oncorex, Sapporo, Japan
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 immunosuppression. 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by Grants-in-Aid for Cancer Research from the Japanese Ministry of Education, Culture, Sports, Science, and Technology.
2 Current address: Department of Molecular and Cellular Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030
3 Address correspondence and reprint requests to Dr. Masanobu Kobayashi, Oncorex, Kita-21, Nishi-12, Kita-Ku, Colabo-Hokkaido, Sapporo, Japan. E-mail address: mkobaya{at}igm.hokudai.ac.jp
4 Abbreviations used in this paper: DC, dendritic cell; APL, acute promyelocytic leukemia; ATRA, all-trans retinoic acid; DLN, draining lymph node; ECM, extracellular matrix; MMP, matrix metalloproteinase; MT, membrane type; TIMP, tissue inhibitor of matrix metalloproteinase.
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