Reciprocal relationship between cancer stem cells and myeloid-derived suppressor cells: implications for tumor progression and therapeutic strategies.

Recently, there has been an increased focus on cancer stem cells (CSCs) due to their resilience, making them difficult to eradicate. This resilience often leads to tumor recurrence and metastasis. CSCs adeptly manipulate their surroundings to create an environment conducive to their survival. In this environment, myeloid-derived suppressor cells (MDSCs) play a crucial role in promoting epithelial-mesenchymal transition and bolstering CSCs' stemness. In response, CSCs attract MDSCs, enhancing their infiltration, expansion and immunosuppressive capabilities. This interaction between CSCs and MDSCs increases the difficulty of antitumor therapy. In this paper, we discuss the interplay between CSCs and MDSCs based on current research and highlight recent therapeutic strategies targeting either CSCs or MDSCs that show promise in achieving effective antitumor outcomes.

Cancer stem cells (CSCs) are a kind of tumor cell. These cells are hard to kill but contribute to tumor progression and metastasis. Myeloid-derived suppressor cells (MDSCs) exist in the tumor tissue and are unfriendly to the antitumor immune response. The interaction between CSCs and MDSCs has a protective effect on tumor progression. Therapeutic strategies targeting CSCs or MDSCs present potential to weaken the complex interaction between the two cell types. This review summarizes the current knowledge of CSCs­MDSCs interaction and offers fresh perspectives on the future development of antitumor therapies targeting CSCs or MDSCs.

Prognostic Value of CXCR6 and the Correlation with Immune Infiltration in the Microenvironment of Skin Cutaneous Melanoma.

Increasing evidence has demonstrated that CXCRs are associated with the tumor infiltration of immune cells and regulate the tumor immune response. However, the prognostic value of CXCRs expression in patients with skin cutaneous melanoma (SKCM) remains unclear. In this study, we aimed to investigate the expression characteristics of CXCRs in SKCM tissues, analyze their prognostic value and the correlation with immune cell infiltration. Multiple public databases were used for exploration, including GEPIA2, GSCA, ULCAN, Metascape, STRING, TIMER2.0, HPA, and Cistrome DB database. And a confirmation experiment was conducted on melanoma mice with flow cytometry. Compared with normal tissues, lower expression of CXCR2/7/8 and higher expression of CXCR3/4 were found in SKCM tissues. CXCR3/4/6 were abnormally expressed in each pathological stage. Moreover, CXCRs were closely related to immune-related biological functions, and mainly interacted with CXCLs. The high expression of CXCR3/5/6 indicated better overall survival of patients. Among them, CXCR6 had the most significant prognostic value, and was most related to tumor infiltration of CD8+T cells, which was verified in melanoma mice. Finally, ETS1 and STAT5B were predicted as the transcription factor of CXCR6. Our findings play an important role in the study of prognostic markers in patients with SKCM.

Astragalus polysaccharides promote neural stem cells-derived oligodendrogenesis through attenuating CD8+T cell infiltration in experimental autoimmune encephalomyelitis.

Endogenous neural stem cells (NSCs) have the potential to generate remyelinating oligodendrocytes, which play an important role in multiple sclerosis (MS). However, the differentiation of NSCs into oligodendrocytes is insufficient, which is considered a major cause of remyelination failure. Our previous work reported that Astragalus polysaccharides (APS) had a neuroprotective effect on experimental autoimmune encephalomyelitis (EAE) mice. However, it remains unclear whether APS regulate NSCs differentiation in EAE mice. In this study, our data illustrated that APS administration could promote NSCs in the subventricular zone (SVZ) to differentiate into oligodendrocytes. Furthermore, we found that APS significantly improved neuroinflammation and inhibited CD8+T cell infiltration into SVZ of EAE mice. We also found that MOG35-55-specific CD8+T cells suppressed NSCs differentiation into oligodendrocytes by secreting IFN-γ, and APS facilitated the differentiation of NSCs into oligodendrocytes which was related to decreased IFN-γ secretion. In addition, APS treatment did not show a better effect on the NSCs-derived oligodendrogenesis after CD8+T cell depletion. This present study demonstrated that APS alleviated neuroinflammation and CD8+T cell infiltration into SVZ to induce oligodendroglial differentiation, and thus exerted neuroprotective effect. Our findings revealed that reducing the infiltration of CD8+T cells might contribute to enhancing NSCs-derived neurogenesis. And APS might be a promising drug candidate to treat MS.

A Recombinant Oncolytic Pseudorabies Virus Expressing Interleukin-18, Interferon-Gamma and PH20 Genes Promotes Systemic Antitumor Immunity.

Pseudorabies virus (PRV) is considered to be a promising oncolytic virus that has potential as a cancer gene therapy drug. In this study, PRV-DCD-1-70 was used as a vector to carry exogenous genes IL-18, IFN-γ and PH20 to construct novel recombinant PRV, rPRV-PH20 and rPRV-IL-18-γ-PH20, and their tumorolytic effects were evaluated in vitro and in vivo. Our study showed that recombinant PRV lysed all four tumor cell lines, Pan02, EMT-6, CT26 and H446, and rPRV-IL-18-γ-PH20 showed the best tumor lysis effect. Further studies in mice bearing Pan02 tumors showed that recombinant PRV, especially rPRV-IL-18-γ-PH20, were able to inhibit tumor growth. Moreover, an immunohistochemical analysis indicated that the recombinant PRV effectively increased the infiltration of CD4+T and CD8+T cells and enhanced the anti-tumor immune response of the organism in vivo. Overall, PRV carrying PH20 and IL-18-γ exogenous genes demonstrated anti-tumor effects, providing a foundation for the further development and application of PRV as a novel tumor oncolytic virus vector.

Suppression of stemness and enhancement of chemosensibility in the resistant melanoma were induced by Astragalus polysaccharide through PD-L1 downregulation.

Chemotherapy is commonly used in the clinical treatment of melanoma, but it is prone to resistance leading to the poor effectiveness. The mechanisms of resistance are complicated including the cancer stemness. Astragalus polysaccharide (APS) is one of the active components of traditional Chinese herbal medicine Astragalus Membranaceus. Our previous work was reported that APS had an inhibitory effect on the stemness of melanoma. In this study we established chemo-resistant melanoma cells and found that expression of stemness genes were upregulated in the resistant melanoma cells. And APS could downregulate expression of stemness genes. Furthermore, APS combined with cisplatin (DDP) could significantly slow down the tumor growth in the mouse model induced by DDP-resistant cells. In addition, we found that programmed death-ligand 1 (PD-L1) expression could be downregulated and the PI3K/AKT signaling could be affected by APS. These results suggested that APS could be a potential candidate in combination with chemotherapeutic agents, which might play a role in reducing the occurrence of resistance and improving the prognosis of melanoma patients.

Immunosuppressive activity is attenuated by Astragalus polysaccharides through remodeling the gut microenvironment in melanoma mice.

Astragalus polysaccharides (APS), the main effective component of Astragalus membranaceus, can inhibit tumor growth, but the underlying mechanisms remain unclear. Previous studies have suggested that APS can regulate the gut microenvironment, including the gut microbiota and fecal metabolites. In this work, our results showed that APS could control tumor growth in melanoma-bearing mice. It could reduce the number of myeloid-derived suppressor cells (MDSC), as well as the expression of MDSC-related molecule Arg-1 and cytokines IL-10 and TGF-ß, so that CD8+ T cells could kill tumor cells more effectively. However, while APS were administered with an antibiotic cocktail (ABX), MDSC could not be reduced, and the growth rate of tumors was accelerated. Consistent with the changes in MDSC, the serum levels of IL-6 and IL-1ß were lowest in the APS group. Meanwhile, we found that fecal suspension from mice in the APS group could also reduce the number of MDSC in tumor tissues. These results revealed that APS regulated the immune function in tumor-bearing mice through remodeling the gut microbiota. Next, we focused on the results of 16S rRNA, which showed that APS significantly regulated most microorganisms, such as Bifidobacterium pseudolongum, Lactobacillus johnsonii and Lactobacillus. According to the Spearman analysis, the changes in abundance of these microorganisms were related to the increase of metabolites like glutamate and creatine, which could control tumor growth. The present study demonstrates that APS attenuate the immunosuppressive activity of MDSC in melanoma-bearing mice by remodeling the gut microbiota and fecal metabolites. Our findings reveal the therapeutic potential of APS to control tumor growth.

Remyelination is enhanced by Astragalus polysaccharides through inducing the differentiation of oligodendrocytes from neural stem cells in cuprizone model of demyelination.

Demyelination is the hallmark of multiple sclerosis (MS). Promoting remyelination is an important strategy to treat MS. Our previous study showed that Astragalus polysaccharides (APS), the main bioactive component of Astragalus membranaceus, could prevent demyelination in experimental autoimmune encephalomyelitis mice. To investigate the effects of APS on remyelination and the underlying mechanisms, in this study we set up a cuprizone-induced demyelination model in mice and treated them with APS. It was found that APS relieved the neurobehavioral dysfunctions caused by demyelination, and efficaciously facilitated remyelination in vivo. In order to determine whether the mechanism of enhancing remyelination was associated with the differentiation of neural stem cells (NSCs), biomarkers of NSCs, astrocytes, oligodendrocytes and neurons were measured in the corpus callosum tissues of mice through Real-time PCR, Western blot and immunohistochemistry assays. Data revealed that APS suppressed the stemness of NSCs, reduced the differentiation of NSCs into astrocytes, and promoted the differentiation into oligodendrocytes and neurons. This phenomenon was confirmed in the differentiation model of C17.2 NSCs cultured in vitro. Since Sonic hedgehog signaling pathway has been proven to be crucial to the differentiation of NSCs into oligodendrocytes, we examined expression levels of the key molecules in this pathway in vivo and in vitro, and eventually found APS activated this signaling pathway. Together, our results demonstrated that APS probably activated Sonic hedgehog signaling pathway first, then induced NSCs to differentiate into oligodendrocytes and promoted remyelination, which suggested that APS might be a potential candidate in treating MS.

Microglia Polarization from M1 toward M2 Phenotype Is Promoted by Astragalus Polysaccharides Mediated through Inhibition of miR-155 in Experimental Autoimmune Encephalomyelitis.

Activated microglia is considered to be major mediators of the neuroinflammatory environment in demyelinating diseases of the central nervous system (CNS). Activated microglia are mainly polarized into M1 type, which plays a role in promoting inflammation and demyelinating. However, the proportion of microglia polarized into M2 type is relatively low, which cannot fully play the role of anti-inflammatory and resistance to demyelinating. Our previous study found that Astragalus polysaccharides (APS) has an immunomodulatory effect and can inhibit neuroinflammation and demyelination in experimental autoimmune encephalomyelitis (EAE), which is a classic animal model of CNS demyelinating disease. In this study, we found that APS was effective in treating EAE mice. It restored microglia balance by inhibiting the polarization of microglia to M1-like phenotype and promoting the polarization of microglia to M2-like phenotype in vivo and in vitro. miR-155 is a key factor in regulating microglia polarization. We found that APS could inhibit the expression level of miR-155 in vivo and in vitro. Furthermore, we performed transfection overexpression and blocking experiments. The results showed that miR-155 mediated the polarization of microglia M1/M2 phenotype, while the selective inhibitor of miR-155 attenuated the inhibition of APS on microglia M1 phenotype and eliminated the promotion of APS on microglia M2 phenotype. Microglia can secrete IL-1α, TNF-α, and C1q after polarizing into M1 type and induce the activation of A1 neurotoxic astrocytes, further aggravating neuroinflammation and demyelination. APS reduced the secretion of IL-1α, TNF-α, and C1q by activated microglia, thus inhibited the formation of A1 neurotoxic astrocytes. In summary, our study suggests that APS regulates the polarization of microglia from M1 to M2 phenotype by inhibiting the miR-155, reduces the secretion of inflammatory factors, and inhibits the activation of neurotoxic astrocytes, thus effectively treating EAE.

The PD-1/PD-Ls pathway is up-regulated during the suppression of experimental autoimmune encephalomyelitis treated by Astragalus polysaccharides.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of CNS. Astragalus polysaccharides (APS), the main active extract from astragalus membranaceus which is a kind of traditional Chinese medicinal herb, is associated with a variety of immunomodulatory activities. We have evaluated the therapeutic effects of APS in the animal model of MS, experimental autoimmune encephalomyelitis (EAE). It was found that APS could effectively alleviate EAE through inhibiting MOG35-55-specific T cell proliferation and reducing the expression of proinflammatory cytokines, which is mediated by up-regulating the expression of PD-1/PD-Ls signaling pathway. Our results demonstrated that EAE could be suppressed significantly by APS administration. It indicated that APS might be a potential of developing innovative drug for the therapy of MS.

Low temperature biosynthesis of Li2O-MgO-P2O5-TiO2 nanocrystalline glass with mesoporous structure exhibiting fast lithium ion conduction.

We demonstrate a biomimetic synthesis methodology that allows us to create Li2O-MgO-P2O5-TiO2 nanocrystalline glass with mesoporous structure at lower temperature. We design a 'nanocrystal-glass' configuration to build a nanoarchitecture by means of yeast cell templates self-assembly followed by the controlled in-situ biomineralization of materials on the cell wall. Electrochemically active nanocrystals are used as the lamellar building blocks of mesopores, and the semiconductive glass phase can act both as the 'glue' between nanocrystals and functionalized component. The Li2O-MgO-P2O5-TiO2 nanocrystalline glass exhibits outstanding thermal stability, high conductivity and wide potential window. This approach could be applied to many other multicomponent glass-ceramics to fabricate mesoporous conducting materials for solid-state lithium batteries.