A Miscibility Study of p(MMA-co-HEMA)-Based Polymer Blends by Thermal Analysis and Solid-State NMR Relaxometry.

Ternary amorphous solid dispersions (ASDs) consist of a multicomponent carrier with the aim of improving physical stability or dissolution performance. A polymer blend as a carrier that combines a water-insoluble and a water-soluble polymer may delay the drug release rate, minimizing the risk of precipitation from the supersaturated state. Different microstructures of the ternary ASD may result in different drug release performances; hence, understanding the phase morphology of the polymer blend is crucial prior to drug incorporation. The objective of this study is to investigate the miscibility of the water-insoluble p(MMA-co-HEMA) and water-soluble polymers such as HPC, HPMC, HPMC-AS, and Soluplus. To prepare the polymer blends, p(MMA-co-HEMA) was spray dried in 80/20 and 90/10 (w/w) ratios with one of the water-soluble polymers. Thermal analysis (mDSC and DMA) and solid-state (ss)NMR relaxometry were applied to study the miscibility of these blends. No conclusions regarding miscibility could be drawn from the Tg measurements by thermal analysis. However, phase-separation could be demonstrated in all blends by ssNMR relaxometry. Moreover, by measuring both the T1ρH and T1H relaxation times, domain sizes between 5 and 50 nm could be estimated. This work shows the importance of using complementary analytical techniques to investigate polymer miscibility.

CSF1R Ligands Expressed by Murine Gliomas Promote M-MDSCs to Suppress CD8+ T Cells in a NOS-Dependent Manner.

Glioblastoma (GBM) is the most common malignant primary brain tumor, resulting in poor survival despite aggressive therapies. GBM is characterized by a highly heterogeneous and immunosuppressive tumor microenvironment (TME) made up predominantly of infiltrating peripheral immune cells. One significant immune cell type that contributes to glioma immune evasion is a population of immunosuppressive cells, termed myeloid-derived suppressor cells (MDSCs). Previous studies suggest that a subset of myeloid cells, expressing monocytic (M)-MDSC markers and dual expression of chemokine receptors CCR2 and CX3CR1, utilize CCR2 to infiltrate the TME. This study evaluated the mechanism of CCR2+/CX3CR1+ M-MDSC differentiation and T cell suppressive function in murine glioma models. We determined that bone marrow-derived CCR2+/CX3CR1+ cells adopt an immune suppressive cell phenotype when cultured with glioma-derived factors. Glioma-secreted CSF1R ligands M-CSF and IL-34 were identified as key drivers of M-MDSC differentiation while adenosine and iNOS pathways were implicated in the M-MDSC suppression of T cells. Mining a human GBM spatial RNAseq database revealed a variety of different pathways that M-MDSCs utilize to exert their suppressive function that is driven by complex niches within the microenvironment. These data provide a more comprehensive understanding of the mechanism of M-MDSCs in glioblastoma.

Identification of susceptibility modules and characteristic genes to osteoarthritis by WGCNA.

The susceptibility modules and characteristic genes of patients with osteoarthritis (OA) were determined by weighted gene co-expression network analysis (WGCNA), and the role of immune cells in OA related microenvironment was analyzed. GSE98918 and GSE117999 data sets are from GEO database. R language was used to conduct difference analysis for the new data set after merging. The formation of gene co-expression network, screening of susceptibility modules and screening of core genes are all through WGCNA. GO and KEGG enrichment analyses were used for Hub genes. The characteristic genes of the disease were obtained by Lasso regression screening. SSGSEA was used to estimate immune cell abundance in sample and a series of correlation analyses were performed. WGCNA was used to form 6 gene co-expression modules. The yellow-green module is identified as the susceptible module of OA. 202 genes were identified as core genes. Finally, RHOT2, FNBP4 and NARF were identified as the characteristic genes of OA. The results showed that the characteristic genes of OA were positively correlated with plasmacytoid dendritic cells, NKT cells and immature dendritic cells, but negatively correlated with active B cells. MDSC were the most abundant immune cells in cartilage. This study identified the Hippo signaling pathway, mTOR signaling pathway, and three characteristic genes (RHOT2, FNBP4, NARF) as being associated with osteoarthritis (OA). These three genes are downregulated in the cartilage of OA patients and may serve as biomarkers for early diagnosis and targeted therapy. Proper regulation of immune cells may aid in the treatment of OA. Future research should focus on developing tools to detect these genes and exploring their therapeutic applications.

Targeting Myeloid-Derived Suppressor Cells via Dual-Antibody Fluorescent Nanodiamond Conjugate.

Fluorescent nanodiamonds (FNDs) are carbon-based nanomaterials that emit bright, photostable fluorescence and exhibit a modifiable surface chemistry. Myeloid-derived suppressor cells (MDSCs) are an immunosuppressive cell population known to expand in cancer patients and contribute to worse patient outcomes. To target MDSC, glycidol-coated FND were conjugated with antibodies against the murine MDSC markers, CD11b and GR1 (dual-Ab FND). In vitro, dual-Ab FND uptake by murine MDSC was significantly higher than IgG-coated FND (94.7% vs. 69.0%, p < 0.05). In vivo, intra-tumorally injected dual-Ab FND primarily localized to the tumor 2 and 24 h post-injection, as measured by in vivo fluorescence imaging and flow cytometry analysis of the spleen and tumor. Dual-Ab FND were preferentially taken up by intra-tumoral MDSC, representing 87.1% and 83.0% of FND+ cells in the tumor 2 and 24 h post-injection, respectively. Treatment of mice with anti-PD-L1 immunotherapy prior to intra-tumoral injection of dual-Ab FND did not significantly alter the uptake of FND by MDSC. These results demonstrate the ability of our novel dual-antibody conjugated FND to target MDSC and reveal a potential strategy for targeted delivery to other specific immune cell populations in future cancer research.

The NF-κB1/p50 Subunit Influences the Notch/IL-6-Driven Expansion of Myeloid-Derived Suppressor Cells in Murine T-Cell Acute Lymphoblastic Leukemia.

T-cell acute lymphoblastic leukemia is an aggressive neoplasia due to hyper-proliferation of lymphoid progenitors and lacking a definitive cure to date. Notch-activating mutations are the most common in driving disease onset and progression, often in combination with sustained activity of NF-κB. Myeloid-derived suppressor cells represent a mixed population of immature progenitors exerting suppression of anti-cancer immune responses in the tumor microenvironment of many malignancies. We recently reported that in a transgenic murine model of Notch3-dependent T-cell acute lymphoblastic leukemia there is an accumulation of myeloid-derived suppressor cells, dependent on both Notch signaling deregulation and IL-6 production inside tumor T-cells. However, possible interaction between NF-κB and Notch in this context remains unexplored. Interestingly, we also reported that Notch3 transgenic and NF-κB1/p50 deleted double mutant mice display massive myeloproliferation. Here, we demonstrated that the absence of the p50 subunit in these mice dramatically enhances the induction and suppressive function of myeloid-derived suppressor cells. This runs in parallel with an impressive increase in IL-6 concentration in the peripheral blood serum, depending on IL-6 hyper-production by tumor T-cells from double mutant mice. Mechanistically, IL-6 increase relies on loss of the negative control exerted by the p50 subunit on the IL-6 promoter. Our results reveal the Notch/NF-κB cross-talk in regulating myeloid-derived suppressor cell biology in T-cell leukemia, highlighting the need to consider carefully the pleiotropic effects of NF-κB-based therapy on the tumor microenvironment.

Myeloid-derived suppressor cells in cancer: Current knowledge and future perspectives.

MDSCs (myeloid-derived suppressor cells) are crucial for immune system evasion in cancer. They accumulate in peripheral blood and tumor microenvironment, suppressing immune cells like T-cells, natural killer cells and dendritic cells. They promote tumor angiogenesis and metastasis by secreting cytokines and growth factors and contribute to a tumor-promoting environment. The accumulation of MDSCs in cancer patients has been linked to poor prognosis and resistance to various cancer therapies. Targeting MDSCs and their immunosuppressive mechanisms may improve treatment outcomes and enhance immune surveillance by developing drugs that inhibit MDSC function, by preventing their accumulation and by disrupting the tumor-promoting environment. This review presents a detailed overview of the MDSC research in cancer with regulation of their development and function. The relevance of MDSC as a prognostic and predictive biomarker in different types of cancers, along with recent advancements on the therapeutic approaches to target MDSCs are discussed in detail.

Eliminating a barrier: Aiming at VISTA, reversing MDSC-mediated T cell suppression in the tumor microenvironment.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment by producing remarkable clinical outcomes for patients with various cancer types. However, only a subset of patients benefits from immunotherapeutic interventions due to the primary and acquired resistance to ICIs. Myeloid-derived suppressor cells (MDSCs) play a crucial role in creating an immunosuppressive tumor microenvironment (TME) and contribute to resistance to immunotherapy. V-domain Ig suppressor of T cell activation (VISTA), a negative immune checkpoint protein highly expressed on MDSCs, presents a promising target for overcoming resistance to current ICIs. This article provides an overview of the evidence supporting VISTA's role in regulating MDSCs in shaping the TME, thus offering insights into how to overcome immunotherapy resistance.

S100A9 and HMGB1 orchestrate MDSC-mediated immunosuppression in melanoma through TLR4 signaling.

BACKGROUND: Immunotherapies for malignant melanoma are challenged by the resistance developed in a significant proportion of patients. Myeloid-derived suppressor cells (MDSC), with their ability to inhibit antitumor T-cell responses, are a major contributor to immunosuppression and resistance to immune checkpoint therapies in melanoma. Damage-associated molecular patterns S100A8, S100A9, and HMGB1, acting as toll like receptor 4 (TLR4) and receptor for advanced glycation endproducts (RAGE) ligands, are highly expressed in the tumor microenvironment and drive MDSC activation. However, the role of TLR4 and RAGE signaling in the acquisition of MDSC immunosuppressive properties remains to be better defined. Our study investigates how the signaling via TLR4 and RAGE as well as their ligands S100A9 and HMGB1, shape MDSC-mediated immunosuppression in melanoma. METHODS: MDSC were isolated from the peripheral blood of patients with advanced melanoma or generated in vitro from healthy donor-derived monocytes. Monocytes were treated with S100A9 or HMGB1 for 72 hours. The immunosuppressive capacity of treated monocytes was assessed in the inhibition of T-cell proliferation assay in the presence or absence of TLR4 and RAGE inhibitors. Plasma levels of S100A8/9 and HMGB1 were quantified by ELISA. Single-cell RNA sequencing (scRNA-seq) was performed on monocytes from patients with melanoma and healthy donors. RESULTS: We showed that exposure to S100A9 and HMGB1 converted healthy donor-derived monocytes into MDSC through TLR4 signaling. Our scRNA-seq data revealed in patient monocytes enriched inflammatory genes, including S100 and those involved in NF-κB and TLR4 signaling, and a reduced major histocompatibility complex II gene expression. Furthermore, elevated plasma S100A8/9 levels correlated with shorter progression-free survival in patients with melanoma. CONCLUSIONS: These findings highlight the critical role of TLR4 and, to a lesser extent, RAGE signaling in the conversion of monocytes into MDSC-like cells, underscore the potential of targeting S100A9 to prevent this conversion, and highlight the prognostic value of S100A8/9 as a plasma biomarker in melanoma.

The combination of apatinib and antigen-specific DC-induced T cells exert antitumor effects by potently improving the immune microenvironment of osteosarcoma.

Objective: Osteosarcoma (OS) is the most common primary bone sarcoma with a high propensity for local invasion and metastasis. Although the antitumor effect of apatinib has been well confirmed in advanced OS, the synergistic effect of apatinib and immunotherapies has not yet been elucidated. Methods: In this study, we established tumour-bearing mice and observed tumour size with low and high doses of apatinib treatments. The expression of 17 cytokines, including vascular endothelial growth factor (VEGF), was detected by protein microarray analysis. Moreover, we designed apatinib and antigen-specific dendritic cell (DC)-T combination treatment for tumour-bearing mice. Tumour growth was detected by statistical analysis of tumour size and microvessel density (MVD) counting, the protein expression of VEGF by western blotting, the cytokines interleukin 6 (IL-6), IL-17 and interferon-gamma (IFN-γ) by enzyme-linked immunosorbent assay (ELISA), and the numbers of myeloid-derived suppressor cells (MDSCs) and tumour-infiltration macrophages (TAMs) by flow cytometry. Results: The results showed that apatinib efficiently suppressed tumour growth, and high-dose apatinib achieved a stronger effect. The same was true for DC-T immunotherapy. However, their combination treatment revealed a better oncolytic effect. Meanwhile, apatinib or DC-T treatment inhibited the expression of VEGF and the proangiogenic mediators IL-6 and IL-17 but increased IFN-γ production. Combination therapy further reduced/increased these effects. In addition, the combination treatment reduced MDSC but enhanced TAM-M1 ratios in the OS microenvironment. These findings indicated that apatinib and antigen-specific DC-T combination therapy was more efficient in oncolysis by regulating pro-/anti-angiogenic inducers and improving the immune state in the OS microenvironment. Conclusion: This study proved that it was feasible to employ immunotherapy with therapeutic agents in OS treatment, which may provide a new approach in addition to the combination of surgery with chemotherapy in tumour treatment.

MAPK signaling pathway induced LOX-1+ polymorphonuclear myeloid-derived suppressor cells in biliary atresia.

Biliary atresia (BA) is a severe pediatric liver disease characterized by progressive bile duct destruction and fibrosis, leading to significant liver damage and frequently necessitating liver transplantation. This study elucidates the role of LOX-1+ polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in BA pathogenesis and assesses their potential as non-invasive early diagnostic biomarkers. Using flow cytometry, immunofluorescence, and molecular profiling, we analyzed the expression and activity of these cells in peripheral blood and liver tissues from BA patients and controls. Our findings reveal a significant increase in the frequencies and function of LOX-1+PMN-MDSCs in BA patients, along with MAPK signaling pathway upregulation, indicating their involvement in disease mechanisms. Additionally, the frequencies of LOX-1+PMN-MDSC in peripheral blood significantly positively correlate with liver function parameters in BA patients, demonstrating diagnostic performance comparable to traditional serum markers. These findings suggest that LOX-1+PMN-MDSCs contribute to the immunosuppressive environment in BA and could serve as potential diagnostic targets.

Host ANGPTL2 establishes an immunosuppressive tumor microenvironment and resistance to immune checkpoint therapy.

Use of immune checkpoint inhibitors (ICIs) as cancer immunotherapy has advanced rapidly in the clinic; however, mechanisms underlying resistance to ICI therapy, including impaired T cell infiltration, low immunogenicity, and tumor "immunophenotypes" governed by the host, remain unclear. We previously reported that in some cancer contexts, tumor cell-derived angiopoietin-like protein 2 (ANGPTL2) has tumor-promoting functions. Here, we asked whether ANGPTL2 deficiency could enhance antitumor ICI activity in two inflammatory contexts: a murine syngeneic model of colorectal cancer and a mouse model of high-fat diet (HFD)-induced obesity. Systemic ANGPTL2 deficiency potentiated ICI efficacy in the syngeneic model, supporting an immunosuppressive role for host ANGPTL2. Relevant to the mechanism, we found that ANGPTL2 induces pro-inflammatory cytokine production in adipose tissues, driving generation of myeloid-derived suppressor cells (MDSCs) in bone marrow and contributing to an immunosuppressive tumor microenvironment and resistance to ICI therapy. Moreover, HFD-induced obese mice showed impaired responsiveness to ICI treatment, suggesting that obesity-induced chronic inflammation facilitated by high ANGPTL2 expression blocks ICI antitumor effects. Our findings overall provide novel insight into protumor ANGPTL2 functions and illustrate the essential role of the host system in ICI responsiveness.

Platelet-activating factor (PAF) promotes immunosuppressive neutrophil differentiation within tumors.

Chronic inflammatory milieu in the tumor microenvironment (TME) leads to the recruitment and differentiation of myeloid-derived suppressor cells (MDSCs). Polymorphonuclear (PMN)-MDSCs, which are phenotypically and morphologically defined as a subset of neutrophils, cause major immune suppression in the TME, posing a significant challenge in the development of effective immunotherapies. Despite recent advances in our understanding of PMN-MDSC functions, the mechanism that gives rise to immunosuppressive neutrophils within the TME remains elusive. Both in vivo and in vitro, newly recruited neutrophils into the tumor sites remained activated and highly motile for several days and developed immunosuppressive phenotypes, as indicated by increased arginase 1 (Arg1) and dcTrail-R1 expression and suppressed anticancer CD8 T cell cytotoxicity. The strong suppressive function was successfully recapitulated by incubating naive neutrophils with cancer cell culture supernatant in vitro. Cancer metabolite secretome analyses of the culture supernatant revealed that both murine and human cancers released lipid mediators to induce the differentiation of immunosuppressive neutrophils. Liquid chromatography-mass spectrometry (LC-MS) lipidomic analysis identified platelet-activation factor (PAF; 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) as a common tumor-derived lipid mediator that induces neutrophil differentiation. Lysophosphatidylcholine acyltransferase 2 (LPCAT2), the PAF biosynthetic enzyme, is up-regulated in human pancreatic ductal adenocarcinoma (PDAC) and shows an unfavorable correlation with patient survival across multiple cancer types. Our study identifies PAF as a lipid-driven mechanism of MDSC differentiation in the TME, providing a potential target for cancer immunotherapy.

Immunosuppressive MDSC and Treg signatures predict prognosis and therapeutic response in glioma.

Glioma, a complex and aggressive brain tumor, is characterized by dysregulated immune responses within the tumor microenvironment (TME). We conducted a comprehensive analysis to elucidate the roles of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in glioma progression and their impact on the immune landscape. Using transcriptome data, we stratified glioma samples based on MDSC and Treg levels, revealing significant differences in patient survival probabilities. LASSO regression identified a gene panel associated with glioma prognosis, yielding a patient-specific risk score. Multivariate Cox regression confirmed the risk score's correlation with overall survival. An ISS (immune suppressive score) system assessed the immune landscape's impact on glioma progression and therapeutic response. Functional validation showed MDSC and Treg infiltration's relevance in glioma progression and immune modulation. Hub genes in the black module, including CCL2, LINC01503, CXCL8, CLEC2B, TIMP1, and RGS2, were identified through MCODE analysis. RGS2 expression correlated with immune cell populations and varied in glioma cells. This study sheds light on MDSCs' and Tregs' roles in glioma pathogenesis, suggesting their potential as prognostic biomarkers and therapeutic targets for personalized immunotherapeutic strategies in glioma treatment.

IRF8-driven reprogramming of the immune microenvironment enhances anti-tumor adaptive immunity and reduces immunosuppression in murine glioblastoma.

BACKGROUND: Glioblastoma (GBM) has a highly immunosuppressive tumor immune microenvironment (TIME), largely mediated by myeloid-derived suppressor cells (MDSCs). Here, we utilized a retroviral replicating vector (RRV) to deliver Interferon Regulatory Factor 8 (IRF8), a master regulator of type 1 conventional dendritic cell (cDC1) development, in a syngeneic murine GBM model. We hypothesized that RRV-mediated delivery of IRF8 could "reprogram" intratumoral MDSCs into antigen-presenting cells (APCs) and thereby restore T-cell responses. METHODS: Effects of RRV-IRF8 on survival and tumor growth kinetics were examined in the SB28 murine GBM model. Immunophenotype was analyzed by flow cytometry and gene expression assays. We assayed functional immunosuppression and antigen presentation by ex vivo T-cell-myeloid co-culture. RESULTS: Intratumoral injection of RRV-IRF8 in mice bearing intracerebral SB28 glioma significantly suppressed the tumor growth and prolonged survival. RRV-IRF8 treated tumors exhibited significant enrichment of cDC1s and CD8+ T-cells. Additionally, myeloid cells derived from RRV-IRF8 tumors showed decreased expression of the immunosuppressive markers Arg1 and IDO1 and demonstrated reduced suppression of naïve T-cell proliferation in ex vivo co-culture, compared to controls. Furthermore, DCs from RRV-IRF8 tumors showed increased antigen presentation compared to those from control tumors. In vivo treatment with azidothymidine (AZT), a viral replication inhibitor, showed that IRF8 transduction in both tumor and non-tumor cells is necessary for survival benefit, associated with a reprogrammed, cDC1- and CD8 T-cell-enriched TIME. CONCLUSIONS: Our results indicate that reprogramming of glioma-infiltrating myeloid cells by in vivo expression of IRF8 may reduce immunosuppression and enhance antigen presentation, achieving improved tumor control.

Sex-Dependent T Cell Dysregulation in Mice with Diet-Induced Obesity.

Obesity is an emerging public health problem. Chronic low-grade inflammation is considered a major promotor of obesity-induced secondary diseases such as cardiovascular and fatty liver disease, type 2 diabetes mellitus, and several cancer entities. Most preliminary studies on obesity-induced immune responses have been conducted in male rodents. Sex-specific differences between men and women in obesity-induced immune dysregulation have not yet been fully outlined but are highly relevant to optimizing prevention strategies for overweight-associated complications. In this study, we fed C57BL/6 female vs. male mice with either standard chow or an obesity-inducing diet (OD). Blood and spleen immune cells were isolated and analyzed by flow cytometry. Lean control mice showed no sex bias in systemic and splenic immune cell composition, whereas the immune responses to obesity were significantly distinct between female and male mice. While immune cell alterations in male OD mice were characterized by a significant reduction in T cells and an increase in myeloid-derived suppressor cells (MDSC), female OD mice displayed preserved T cell numbers. The sex-dependent differences in obesity-induced T cell dysregulation were associated with varying susceptibility to body weight gain and fatty liver disease: Male mice showed significantly more hepatic inflammation and histopathological stigmata of fatty liver in comparison to female OD mice. Our findings indicate that sex impacts susceptibility to obesity-induced T cell dysregulation, which might explain sex-dependent different incidences in the development of obesity-associated secondary diseases. These results provide novel insights into the understanding of obesity-induced chronic inflammation from a sex-specific perspective. Given that most nutrition, exercise, and therapeutic recommendations for the prevention of obesity-associated comorbidities do not differentiate between men and women, the data of this study are clinically relevant and should be taken into consideration in future trials and treatment strategies.

Immune profiling of premalignant lesions in patients with Peutz-Jeghers syndrome.

BACKGROUND: Peutz-Jeghers syndrome (PJS), is a rare autosomal dominant hereditary disease characterized by an elevated risk of various cancers. Serine/Threonine Kinase 11 (STK11) gene is a major tumor suppressor crucial for immune evasion with and beyond tumorigenic cells. It has garnered increasing attention in the realm of oncology treatment, particularly in the context of immunotherapy development. OBJECTIVE: This study aimed to assess the suitability of polyps obtained from individuals with PJS, resulting from germline STK11 deficiency, for immunotherapy. Additionally, we seek to identify potential shared mechanisms related to immune evasion between PJS polyps and cancers. To achieve this, we examined PJS polyps alongside familial adenomatous polyposis (FAP) and sporadic polyps. METHODS: Polyps were compared among themselves and with either the paracancerous tissues or colon cancers. Pathological and gene expression profiling approaches were employed to characterize infiltrating immune cells and assess the expression of immune checkpoint genes. RESULTS: Our findings revealed that PJS polyps exhibited a closer resemblance to cancer tissues than other polyps in terms of their immune microenvironment. Notably, PJS polyps displayed heightened expression of the immune checkpoint gene CD80 and an accumulation of myeloid cells, particularly myeloid-derived suppressor cells (MDSCs). CONCLUSION: The findings suggest an immunobiological foundation for the increased cancer susceptibility in PJS patients, paving the way for potential immune therapy applications in this population. Furthermore, utilizing PJS as a model may facilitate the exploration of immune evasion mechanisms, benefiting both PJS and cancer patients.

VEGFA contributes to tumor property of glioblastoma cells by promoting differentiation of myeloid-derived suppressor cells.

BACKGROUND: Glioblastoma (GBM) is a malignant astrocytic tumor and its progression involves the regulation of vascular endothelial growth factor-A (VEGFA). However, the mechanism of VEGFA in regulating GBM progression remains unclear. METHODS: VEGFA mRNA expression was analyzed by quantitative real-time polymerase chain reaction. Protein expression of VEGFA, cluster of differentiation 9 (CD9), CD81, and transforming growth factor-ß1 (TGF-ß1) was detected by western blotting assay. Flow cytometry assay was conducted to assess cell proliferation, cell apoptosis and myeloid-derived suppressor cell (MDSC) differentiation. TUNEL cell apoptosis detection kit was utilized to analyze cell apoptosis of tumors. Angiogenic capacity was investigated by tube formation assay. Transwell assay was used to assess cell migration and invasion. The effect of VEGFA on tumor formation was determined by a xenograft mouse model assay. Immunohistochemistry assay was used to analyze positive expression rate of VEGFA in tumor tissues. TGF-ß1 level was detected by enzyme-linked immunosorbent assay. RESULTS: VEGFA expression was upregulated in GBM tissues, GBM cells, and exosomes from GBM patients and GBM cells. VEGFA silencing led to decreased cell proliferation, tube formation, migration and invasion and increased cell apoptosis. Moreover, VEGFA knockdown also delayed tumor formation. VEGFA promoted MDSC differentiation and TGF-ß1 secretion by MDSCs by being packaged into exosomes. In addition, TGF-ß1 knockdown displayed similar effects with VEGFA silencing on GBM cell phenotypes, and MDSCs attenuated VEGFA knockdown-induced effects by secreting TGF-ß1 in A172 and U251 cells. CONCLUSION: VEGFA contributed to tumor property of GBM cells by promoting MDSC differentiation and TGF-ß1 secretion by MDSCs, providing potential targets for GBM treatment.

Ferroptosis: mechanism, immunotherapy and role in ovarian cancer.

Ovarian cancer is currently the second most common malignant tumor among gynecological cancers worldwide, primarily due to challenges in early diagnosis, high recurrence rates, and resistance to existing treatments. Current therapeutic options are inadequate for addressing the needs of ovarian cancer patients. Ferroptosis, a novel form of regulated cell death with demonstrated tumor-suppressive properties, has gained increasing attention in ovarian malignancy research. A growing body of evidence suggests that ferroptosis plays a significant role in the onset, progression, and incidence of ovarian cancer. Additionally, it has been found that immunotherapy, an emerging frontier in tumor treatment, synergizes with ferroptosis in the context of ovarian cancer. Consequently, ferroptosis is likely to become a critical target in the treatment of ovarian cancer.

Synergistic effect of TiO2 nanoparticles and poly (ethylene-co-vinyl acetate) on the morphology and crystallization behavior of polylactic acid.

The impact of adding ethylene vinyl acetate copolymer (EVA 80) and 1 wt% TiO2 nanoparticles on the morphology and crystallization behavior of poly(lactic acid) blends was investigated using DSC, SEM, and POM. Thermal analysis revealed the enhancement of crystallinity of PLA in the presence of TiO2 and higher EVA 80 content in the blend. The PLA and EVA 80 components showed compatibility, as evidenced by the shift of the glass transition temperatures of the PLA phase in the blend to lower values compared to neat PLA. The lower temperature shift of the cold crystallization of the PLA and the formation of the small spherulites of the PLA in the blends indicated that the EVA 80 and TiO2 act as a nucleating agent for crystallization. The non-isothermal crystallization parameters of the composites were evaluated using Avrami's modified model, the MO approach, and Friedman's isoconversional method. The Avrami's modified rate constant (K) and the effective activation energy values significantly increased with the incorporation of EVA 80 and TiO2 nanoparticles. Furthermore, the thermogravimetric analysis (TGA) showed improved thermal stability of PLA by adding EVA 80 and TiO2.

Systemically targeting monocytic myeloid-derived suppressor cells using dendrimers and their cell-level biodistribution kinetics.

The focus of nanoparticles in vivo trafficking has been mostly on their tissue-level biodistribution and clearance. Recent progress in the nanomedicine field suggests that the targeting of nanoparticles to immune cells can be used to modulate the immune response and enhance therapeutic delivery to the diseased tissue. In the presence of tumor lesions, monocytic-myeloid-derived suppressor cells (M-MDSCs) expand significantly in the bone marrow, egress into peripheral blood, and traffic to the solid tumor, where they help maintain an immuno-suppressive tumor microenvironment. In this study, we investigated the interaction between PAMAM dendrimers and M-MDSCs in two murine models of glioblastoma, by examining the cell-level biodistribution kinetics of the systemically injected dendrimers. We found that M-MDSCs in the tumor and lymphoid organs can efficiently endocytose hydroxyl dendrimers. Interestingly, the trafficking of M-MDSCs from the bone marrow to the tumor contributed to the deposition of hydroxyl dendrimers in the tumor. M-MDSCs showed different capacities of endocytosing dendrimers of different functionalities in vivo. This differential uptake was mediated by the unique serum proteins associated with each dendrimer surface functionality. The results of this study set up the framework for developing dendrimer-based immunotherapy to target M-MDSCs for cancer treatment.