title: All-trans retinoic acid enhances murine dendritic cell migration to draining lymph nodes via the balance of matrix metalloproteinases and their inhibitors.
abstract: 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.
authors: Division of Cancer-Related Genes, Institute for Genetic Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan
authors: Stephanie
authors: S
authors: Darmanin
authors: Jian
authors: J
authors: Chen
authors: Songji
authors: S
authors: Zhao
authors: Hongyan
authors: H
authors: Cui
authors: Reza
authors: R
authors: Shirkoohi
authors: Naoki
authors: N
authors: Kubo
authors: Yuji
authors: Y
authors: Kuge
authors: Nagara
authors: N
authors: Tamaki
authors: Koji
authors: K
authors: Nakagawa
authors: Jun-ichi
authors: J
authors: Hamada
authors: Tetsuya
authors: T
authors: Moriuchi
authors: Masanobu
authors: M
authors: Kobayashi
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D005260:Female; D005786:Gene Expression Regulation; D008198:Lymph Nodes / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000235:genetics; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: C515371:Ccr7 protein, mouse; D012333:RNA, Messenger; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D019714:Tissue Inhibitor of Metalloproteinases; D014212:Tretinoin; D020782:Matrix Metalloproteinases