Dendritic cells (DCs) can mediate immune responses or immune tolerance depending on their immunophenotype and functional status. Remodeling of DCs’ immune functions can develop proper therapeutic regimens for different immune-mediated diseases. In the immunopathology of autoimmune diseases (ADs), activated DCs notably promote effector T-cell polarization and exacerbate the disease. Recent evidence indicates that metformin can attenuate the clinical symptoms of ADs due to its anti-inflammatory properties. Whether and how the therapeutic effects of metformin on ADs are associated with DCs remain unknown. In this study, metformin was added to a culture system of LPS-induced DC maturation. The results revealed that metformin shifted DC into a tolerant phenotype, resulting in reduced surface expression of MHC-II, costimulatory molecules and CCR7, decreased levels of proinflammatory cytokines (TNF-α and IFN-γ), increased level of IL-10, upregulated immunomodulatory molecules (ICOSL and PD-L) and an enhanced capacity to promote regulatory T-cell (T_reg) differentiation. Further results demonstrated that the anti-inflammatory effects of metformin in vivo were closely related to remodeling the immunophenotype of DCs. Mechanistically, metformin could mediate the metabolic reprogramming of DCs through FoxO3a signaling pathways, including disturbing the balance of fatty acid synthesis (FAS) and fatty acid oxidation (FAO), increasing glycolysis but inhibiting the tricarboxylic acid cycle (TAC) and pentose phosphate pathway (PPP), which resulted in the accumulation of fatty acids (FAs) and lactic acid, as well as low anabolism in DCs. Our findings indicated that metformin could induce tolerance in DCs by reprogramming their metabolic patterns and play anti-inflammatory roles in vitro and in vivo.

Aim and background: Due to the radiosensitivity and deep anatomical location of nasopharyngeal carcinoma (NPC), radiotherapy serves as the cornerstone of standardized treatment for this malignancy. Beyond its cytotoxic effects, radiotherapy can serve as an immunological adjuvant by inducing immunogenic cell death (ICD). Dendritic cells (DCs), as potent antigen-presenting cells, play a critical role in tumor immunotherapy, but their exact role in the ICD process of NPC remains unclear. The effects of high-dose radiation (≥2 Gy) on DCs and the type of immune response it elicits in NPC have not been fully elucidated.Methods: An in vitro study was conducted to assess whether ICD of NPC 5-8F cells induced by high-dose radiation could regulate the immune response of DCs. Specifically, the maturation and antigen-presenting capacity of DCs were evaluated following co-culture with NPC cells exposed to high-dose radiation.Results: High-dose radiation was found to induce ICD in NPC 5-8F cells, as evidenced by increased pro-inflammatory factor levels and reduced anti-inflammatory factor levels in the cell culture supernatant. Co-culture with NPC cells exposed to high-dose radiation for 15 minutes significantly enhanced the expression of surface molecules on DCs, promoting their immune sensitization.Conclusion: High-dose radiation-induced apoptosis of NPC 5-8F cells is a form of ICD, which plays an important role in regulating DC immune function. These findings provide insight into the immunomodulatory effects of radiotherapy in NPC and its potential to enhance tumor immunotherapy through DC activation.

Dendritic cells (DCs), the most potent antigen-presenting cells, play a central role in the initiation, regulation, and maintenance of the immune responses. Vascular endothelial growth factor (VEGF) is one of the important cytokines in the tumor microenvironment (TME) and can inhibit the differentiation and functional maturation of DCs. To elucidate the potential mechanisms of DC dysfunction induced by VEGF, the effects of VEGF on the biophysical characteristics and motility of human mature DCs (mDCs) were investigated. The results showed that VEGF had a negative influence on the biophysical properties, including electrophoretic mobility, osmotic fragility, viscoelasticity, and transmigration. Further cytoskeleton structure analysis by confocal microscope and gene expression profile analyses by gene microarray and real-time PCR indicated that the abnormal remodeling of F-actin cytoskeleton may be the main reason for the deterioration of biophysical properties, motility, and stimulatory capability of VEGF-treated mDCs. This is significant for understanding the biological behavior of DCs and the immune escape mechanism of tumors. Simultaneously, the therapeutic efficacies may be improved by blocking the signaling pathway of VEGF in an appropriate manner before the deployment of DC-based vaccinations against tumors.

Distal metastasis is the main cause of clinical treatment failure in patients with colon cancer. It is now known that the invasion and metastasis of cancer cells is precisely regulated by chemical and physical factors in vivo. However, the role of extracellular matrix (ECM) stiffness in colon cancer cell (CCCs) invasion and metastasis remains unclear. Here, bioinformatical analysis suggested that a high expression level of yes associated protein 1 (YAP1) was significantly associated with metastasis and poor prognosis in colon cancer patients. We further investigated the effects of polyacrylamide hydrogels with different stiffnesses (3, 20, and 38 ​kPa), which were simulated as ECM, on the mechanophenotype (F-actin cytoskeleton organization, electrophoretic rate, membrane fluidity, and Young's modulus) of CCCs. The results showed that a stiffer ECM could induce the maturation of focal adhesions and formation of stress fibers in CCCs, regulate their mechanophenotypes, and promote cell motility. We also demonstrated that the expression levels of YAP1 and paxillin were positively correlated in patients with colon cancer. YAP1 knockdown reduces paxillin clustering and cell motility and alters the cellular mechanophenotypes of CCCs. This is of great significance for an in-depth understanding of the invasion and metastatic mechanisms of colon cancer and for the optimization of clinical therapy from the perspective of mechanobiology.

Dendritic cells (DCs) are the most potent specialized antigen-presenting cells as now known, which play a crucial role in initiating and amplifying both the innate and adaptive immune responses. Immunologically, the motilities and T cell activation capabilities of DCs are closely related to the resulting immune responses. However, due to the complexity of the immune system, the dynamic changes in the number of cells during the peripheral tissue (e.g. skin and mucosa) immune response induced by DCs are still poorly understood. Therefore, this study simulated dynamic number changes of DCs and T cells in this process by constructing several ordinary differential equations and setting the initial conditions of the functions and parameters. The results showed that these equations could simulate dynamic numerical changes of DCs and T cells in peripheral tissue and lymph node, which was in accordance with the physiological conditions such as the duration of immune response, the proliferation rate and the motilities of DCs and T cells. This model provided a theoretical reference for studying the immunologic functions of DCs and practical guidance for the clinical DCs-based therapy against immune-related diseases.