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.

Effect of all-trans retinoic acid on renal expressions of matrix metalloproteinase-2, matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in rats with glomerulosclerosis

“…There was no significant difference in the efficacy of benazepril compared with ATRA in enhancing the expression of MMP-2/MMP-9. There are reports of a similar effects of ATRA: MMP-2 and MMP-9 were found to have increased in murine dendritic cells [25]. Marín et al [26] found that levels of both MMP-2 and MMP-9 were diminished in the renal basement membranes of newborn male rats fed a vitamin A-deficient diet [26].…”

Leukotriene C4 induces migration of human monocyte–derived dendritic cells without loss of immunostimulatory function

“…As such, the increased induction of TIMP-1 in response to PGE 2 probably inhibited the migration-promoting effects of MMP-9, a hypothesis supported by a previous report demonstrating that the balance of MMP-9 and TIMP expression is of crucial for DC migration in vivo. 58 Taken together, we have shown that LTC 4 may represent a promising candidate to replace PGE 2 in DC maturation protocols that may lead to enhanced immunogenicity of DC-based cancer vaccines. The results presented in this study warrant further investigation of this novel maturation protocol in animal tumor models, and ultimately, in clinical trials.…”

Pericyte TIMP3 and ADAMTS1 Modulate Vascular Stability after Kidney Injury

“…16,17 Moreover, proteinases and factors that regulate their activity are now recognized to serve as key regulators of cell migration and spreading in cancer biology and development, model systems that may be instructive in studying kidney injury. [18][19][20] In this study, we investigated the role of kidney pericytes in vascular stabilization and the central role that pericytes play in regulating protease activity of the vasculature.…”