Regulatory T cells (Tregs), which execute their immunosuppressive functions by multiple mechanisms, have been verified to contribute to the tumor microenvironment (TME). Numerous studies have shown that the activation of the CBM complex/NF-κB signaling pathway results in the expression of hypoxia-inducible factor-1 (HIF-1α) and interleukin-6 (IL-6), which initiate the TME formation. HIF-1α and IL-6 promote regulatory T cells (Tregs) proliferation and migration through the MAPK/CDK4/6/Rb and STAT3/SIAH2/P27 signaling pathways, respectively. IL-6 also promotes the production of HIF-1α and enhances the self-regulation of Tregs in the process of tumor microenvironment (TME) formation. In this review, we discuss how the crosstalk between the CARMA1–BCL10–MALT1 signalosome complex (CBM complex)/NF-κB and MAPK/P27 signaling pathways contributes to the formation of the TME, which may provide evidence for potential therapeutic targets in the treatment of solid tumors.
Background: Programmed cell death protein 1 (PD-1), as an immune checkpoint cell membrane receptor, negatively regulates T cell activation via its immune receptor, the tyrosine-based switch motif (ITSM). The purpose of this research was to evaluate the antitumor activity T cells with the ITSM mutation of PD-1 on non-small cell lung cancer (NSCLC) in vitro and in vivo.Methods: In this study, the tyrosine of ITSM in cytotoxic T cells was mutated using the adenine base editor (ABE)-xCas9 system to evaluate its effect on the antitumor activity of T cells against NSCLC. Results: Results showed that the PD-1-deficient T cells enhanced the death of the cocultured NSCLC cells compared with the normal T cells and saline solution. PD-1-deficient T cells also changed the interleukin 2(IL-2), interferon γ (IFN-γ), tumor necrosis factor α (TNF-α), and granulocyte-macrophage colony-stimulating factor (GM-CSF) secretion of T cells compared with those of the normal T cells. The effectiveness of ITSM mutation in enhancing the antitumor activity of PD-1-deficient T cells was verified in vivo by using a mouse xenograft model. The xenografted mice treated with PD-1-deficient T cells demonstrated repressed tumor growth of the NSCLC cells compared with those treated with normal T cells and saline solution. Conclusions: The mutation of ITSM in cytotoxic T cell via the ABE-xCas9 system can significantly enhance the antitumor activity of T cells.
Background: Methylmercury (MeHg), manganese ions (Mn 2+ ), and lead ions (Pb 2+ ) are ubiquitous environmental pollutants and may be neurotoxic especially during fetal development. We decided to explore the toxic mechanisms of MeHg (organic heavy metals), Mn 2+ (inorganic heavy metals) and Mn 2+ on the proliferation and differentiation of human neural stem cells (hNSCs). Materials and Methods: The proliferation and apoptosis of hNSCs were analyzed via CCK-8 method and flow cytometry under MeHg, Mn 2+ and Pb 2+ , respectively. RNA-seq was used for analyzing proliferation/differentiation mechanism of MeHg, Mn 2+ and Pb 2+ stressing hNSCs. Results: Our experiment found that when hNSCs were exposed to below 0.5 nM MeHg, 5μM Mn 2+ and 10 μM Pb 2+ , cell proliferation and differentiation were promoted. Apoptosis rates increased significantly when hNSCS were exposed to exceed 0.5 nM MeHg, 5μM Mn 2+ and 10 μM Pb 2+ . RNA-seq results showed that metal ions altered the genes expression level and signaling pathways of hNSC differentiation and proliferation, but the regulatory mechanisms of MeHg, Mn 2+ and Pb 2+ were different. Conclusion: Our findings indicated that very low-dose metal exposure may deplete hNSC pool by making prematurely differentiated neurons increase, which may be the real cause of long-term nervous system disruption in adulthood, rather than higher metal doses will cause more direct toxicity during infant development.
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