Regulatory effects of matrine on antitumor activity of dendritic cells in the tumor microenvironment
Regulatory effects of matrine on antitumor activity of dendritic cells in the tumor microenvironment
Kianush Charoghdoozi,1Sajad Dehnavi,2Jalil Tavakol Afshari,3Mahvash Sadeghi,4Mojgan Mohammadi,5,*
1. Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran 2. Allergy Research Center, Mashhad University of Medical Sciences, Mashhad, Iran 3. Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran 4. Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran 5. Allergy Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
Introduction: Cancer, which results from the uncontrolled proliferation of cells, is one of the most serious diseases threatening human health. Matrine, an alkaloid isolated from the traditional Chinese medicine Sophora flavescens, has been the subject of numerous studies demonstrating its anticancer activity. It can inhibit cancer cell proliferation, arrest the cell cycle, induce apoptosis, and inhibit cancer cell metastasis. It has also been shown to have an effect on immune cells, including dendritic cells.
Methods: A comprehensive search was conducted using databases such as PubMed, Google Scholar, Medline, Scopus, and Web of Science to identify studies investigating the effect of matrine on the antitumor function of dendritic cells. The search strategy used a combination of keywords, including "matrine", "dendritic cell", "cancer", and "tumor microenvironment (TME) ". A review of the selected studies was performed in order to gain insight into the underlying mechanisms.
Results: Dendritic cells (DCs) are considered to be the most potent antigen presenting cells (APCs). They play a pivotal role in the initiation and regulation of the adaptive immune response, acting as an important link between the innate and adaptive immunity.
Anti-cancer immune responses involving T cells are dependent on antigen presentation by DCs.
Immature DCs recognize signals that stimulate their maturation, including those indicative of damage or pathogen-associated molecular patterns (DAMPs or PAMPs), such as tumor-derived antigens, through pattern recognition receptors (PRR). These antigens are then transported to major histocompatibility complex (MHC) molecules for presentation to T lymphocytes.
This interaction promotes cross-presentation, T cell trafficking to the tumor, and the induction of effector function and memory formation.
Most tumors show the insufficient number of mature DCs, and their presence is associated with a favorable prognosis in murine tumor models and cancer patients. The tumor microenvironment (TME) can inhibit the development of DCs and reduce their ability to initiate the immune responses. Several factors contribute to this mechanism including the production of interleukin (IL)-10 by macrophages in the TME, the capture of DCs by the liver X receptor (LXR), increased indoleamine 2, 3-dioxigenase 1 (IDO1) leading to tryptophan depletion, and the interaction of FMS-like tyrosine kinase 3 (FLT3) and vascular endothelial growth factor (VEGF), which negatively affects DC differentiation and weakens the immune systems to fight tumors.
The study conducted by Wang Jing-kang et al. showed that matrine enhanced the anti-tumor activity of DCs. Matrine was observed to significantly increase the gene expression of toll-like receptor (TLR)7, TLR8, myeloid differentiation factor 88 (MyD88), tumor necrosis factor receptor-associated factor 6 (TRAF-6), and IκB kinase (IKK), as well as the protein levels of TLR7 and TLR8. Additionally, the levels of IL-12, IL-6, and tumor necrosis factor-alpha (TNF-α) were reported to increase by matrine. Moreover the gene expression of MHC-II, CD54, CD80, and CD86 in DCs were increased by matrine. Many studies showed that activated effector T cells had substantial tumor-killing activity.
According to the study by N. Zhou et al., the combination of matrine and the mTOR inhibitor KU0063794 has the potential to enhance DC maturation, T cell proliferation, and cytokine secretion which consequently resulted in a significant increase in the levels of interferon-gamma (IFN-γ) and TNF-α, whereas IL-10 levels were decreased.
In another study conducted by N. Zhou et al., it was demonstrated that matrine could enhance the expression of CD86 and CD83 in a dose-dependent manner. Matrine was observed to promote T cell and DC activation. Furthermore, matrine was found to significantly increase the levels of interferon-γ (IFN-γ), TNF-α, and IL-12p70.
Conclusion: Matrine, a compound derived from traditional Chinese medicine, shows significant potential in enhancing the anti-tumor function of DCs. By modulating key pathways involved in DC maturation and activation, matrine can stimulate the production of pro-inflammatory cytokines, increase antigen presentation in DCs, and promote T cell effector responses.
These findings suggest that matrine with an immune-regulatory effects may be a promising therapeutic agent for cancer treatment. Further research needs for a better understanding of the mechanisms underlying the effects of matrine on the antitumor activity of DCs and other immune cells in the tumor microenvironment.