Myeloid-derived Regulatory Cells Research Articles

Myeloid cell expression of CD200R is modulated in active TB disease and regulates Mycobacterium tuberculosis infection in a biomimetic model.

A robust immune response is required for resistance to pulmonary tuberculosis (TB), the primary disease caused by Mycobacterium tuberculosis (Mtb). However, pharmaceutical inhibition of T cell immune checkpoint molecules can result in the rapid development of active disease in latently infected individuals, indicating the importance of T cell immune regulation. In this study, we investigated the potential role of CD200R during Mtb infection, a key immune checkpoint for myeloid cells. Expression of CD200R was consistently downregulated on CD14+ monocytes in the blood of subjects with active TB compared to healthy controls, suggesting potential modulation of this important anti-inflammatory pathway. In homogenized TB-diseased lung tissue, CD200R expression was highly variable on monocytes and CD11b+HLA-DR+ macrophages but tended to be lowest in the most diseased lung tissue sections. This observation was confirmed by fluorescent microscopy, which showed the expression of CD200R on CD68+ macrophages surrounding TB lung granuloma and found expression levels tended to be lower in macrophages closest to the granuloma core and inversely correlated with lesion size. Antibody blockade of CD200R in a biomimetic 3D granuloma-like tissue culture system led to significantly increased Mtb growth. In addition, Mtb infection in this system reduced gene expression of CD200R. These findings indicate that regulation of myeloid cells via CD200R is likely to play an important part in the immune response to TB and may represent a potential target for novel therapeutic intervention.

Immune modulation in transplant medicine: a comprehensive review of cell therapy applications and future directions.

Balancing the immune response after solid organ transplantation (SOT) and vascularized composite allotransplantation (VCA) remains an ongoing clinical challenge. While immunosuppressants can effectively reduce acute rejection rates following transplant surgery, some patients still experience recurrent acute rejection episodes, which in turn may progress to chronic rejection. Furthermore, these immunosuppressive regimens are associated with an increased risk of malignancies and metabolic disorders. Despite significant advancements in the field, these IS related side effects persist as clinical hurdles, emphasizing the need for innovative therapeutic strategies to improve transplant survival and longevity. Cellular therapy, a novel therapeutic approach, has emerged as a potential pathway to promote immune tolerance while minimizing systemic side-effects of standard IS regiments. Various cell types, including chimeric antigen receptor T cells (CAR-T), mesenchymal stromal cells (MSCs), regulatory myeloid cells (RMCs) and regulatory T cells (Tregs), offer unique immunomodulatory properties that may help achieve improved outcomes in transplant patients. This review aims to elucidate the role of cellular therapies, particularly MSCs, T cells, Tregs, RMCs, macrophages, and dendritic cells in SOT and VCA. We explore the immunological features of each cell type, their capacity for immune regulation, and the prospective advantages and obstacles linked to their application in transplant patients. An in-depth outline of the current state of the technology may help SOT and VCA providers refine their perioperative treatment strategies while laying the foundation for further trials that investigate cellular therapeutics in transplantation surgery.

Elucidating the role of FOS in modulating the immune microenvironment through fibroblast and myeloid cell regulation in locoregional recurrent HNSCC.

Head and neck squamous cell carcinoma (HNSCC) presents a significant clinical challenge, particularly due to its high propensity for locoregional recurrence. Current research underscores the need to unravel the complex interactions within the tumor microenvironment. This study addresses the critical gap in understanding how FOS modulates the immune landscape in HNSCC, with a focus on its influence on fibroblast and myeloid cell dynamics. Employing a comprehensive approach, we analyzed tissue samples from HNSCC patients and adjacent non-cancerous tissues using bulk RNA sequencing complemented by in-depth bioinformatics analyses, including gene ontology (GO), Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis, and immune infiltration assessment. A pivotal aspect of our research involved dissecting single-cell RNA-seq data from GSE234933 to elucidate the cell-type-specific expression of FOS. We found that FOS expression varies significantly in different cell populations in the HNSCC tumor microenvironment, especially in fibroblasts and myeloid cells. This expression difference may reflect the different roles of these cells in tumor progression and their impact on the tumor microenvironment. Our results uncover a significant correlation between FOS expression and key immune and hypoxia-related pathways, suggesting its integral role in the tumor microenvironment. These findings not only enhance our understanding of HNSCC pathogenesis but also highlight FOS as a potential therapeutic target. This study marks a significant step towards addressing the urgent need for targeted interventions in HNSCC, particularly in the context of locoregional recurrence.

Abstract 1385: Crosstalk between hepatocyte and myeloid-specific IL17 signaling in colorectal cancer metastasis

Abstract Advanced colorectal cancer (CRC) is resistant to current immunotherapies and prone to metastasis. Chronic inflammation mediated by cytokines such as interleukin (IL)17 activates the oncogenic pathways in cancer cells, promoting sporadic and inflammation-associated CRC. Increased levels of IL17A in early stages of CRC portends poor prognosis indicating its potential involvement into metastasis. We and others previously showed that IL17A signaling is required for early CRC tumorigenicity in a variety of models and that in early CRC, its ability to signal to epithelial cells is essential. What remains unknown is whether IL17 signaling to other cell types within the tumor microenvironment (TME) is essential to control tumor progression and metastasis. Using a model of colitis-associated cancer (CAC) we found that “late” IL17A neutralization decreases tumor burden, possibly acting through regulation of myeloid cells and chemokine network essential for the control of immunosuppressive TME. Next, using models of colorectal cancer liver metastasis (CRLM) including intraportal cell injection and cecum transplantation of organoids with distinct set of oncogenic mutation we found that IL17 neutralization reduces metastasis. FACS analysis revealed that IL17A promotes the recruitment of tumor-associated macrophages and other key myeloid subsets into the metastatic liver environment. Interestingly, ablation of IL17RC (receptor) in myeloid cells only (using Il17rcf/f -LysMCre mice) led to reduction in metastasis and reshaping of metastatic myeloid cell compartments. Meanwhile, IL17 signaling in hepatocytes was required for early metastasis and pre-metastatic niche formation, as the ablation of IL17RC in hepatocytes (using Il17rcf/f -AlbCre mice) led to a reduction of metastatic numbers but not growth. This coincided with reduced neutrophil recruitment and enhanced activation of cytotoxic innate lymphoid cells and CD8 T lymphocytes, indicating the role of hepatocyte specific IL17 signaling in blunting anti-tumor immunity. Our findings illuminate the role of inflammatory cytokine IL17 into CRC progression and metastasis and imply its distinct cell type specific role within the metastatic liver TME. Citation Format: Katarzyna Chojnacka, Dan Kamen, Katrina M. Reyes, Hana Tomizawa, Sergei I. Grivennikov. Crosstalk between hepatocyte and myeloid-specific IL17 signaling in colorectal cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1385.

Negative Vaccination Strategies for Promotion of Transplant Tolerance.

Organ transplantation requires the use of immunosuppressive medications that lack antigen specificity, have many adverse side effects, and fail to induce immunological tolerance to the graft. The safe induction of tolerance to allogeneic tissue without compromising host responses to infection or enhancing the risk of malignant disease is a major goal in transplantation. One promising approach to achieve this goal is based on the concept of "negative vaccination." Vaccination (or actively acquired immunity) involves the presentation of both a foreign antigen and immunostimulatory adjuvant to the immune system to induce antigen-specific immunity. By contrast, negative vaccination, in the context of transplantation, involves the delivery of donor antigen before or after transplantation, together with a "negative adjuvant" to selectively inhibit the alloimmune response. This review will explore established and emerging negative vaccination strategies for promotion of organ or pancreatic islet transplant tolerance. These include donor regulatory myeloid cell infusion, which has progressed to early-phase clinical trials, apoptotic donor cell infusion that has advanced to nonhuman primate models, and novel nanoparticle antigen-delivery systems.

CD4+ T cells proliferation assay to analyze Mo-MDSCs suppressive function.

Among myeloid regulatory cells (MRCs), some particular subsets termed myeloid-derived suppressor cells (MDSCs) have been described. They are suppressor myeloid cells characterized by their ability to regulate innate and adaptive immune responses and known to accumulate in the context of chronic diseases and cancer. The lack of specific markers makes their classification difficult and requires functional studies to distinguish them from other myeloid cells. In this sense, the in vitro analysis of the proliferation of T lymphocytes cultured with MDSCs provides information about the regulatory function of these cells. Here, we provide a detailed protocol to assess the ability of human Mo-MDSCs to suppress T cell proliferation in vitro after obtaining Mo-MDSCs and CD4+T cell from peripheral blood.

Bruton’s tyrosine kinase inhibition reduces disease severity in a model of secondary progressive autoimmune demyelination

Bruton’s tyrosine kinase (BTK) is an emerging target in multiple sclerosis (MS). Alongside its role in B cell receptor signaling and B cell development, BTK regulates myeloid cell activation and inflammatory responses. Here we demonstrate efficacy of BTK inhibition in a model of secondary progressive autoimmune demyelination in Biozzi mice with experimental autoimmune encephalomyelitis (EAE). We show that late in the course of disease, EAE severity could not be reduced with a potent relapse inhibitor, FTY720 (fingolimod), indicating that disease was relapse-independent. During this same phase of disease, treatment with a BTK inhibitor reduced both EAE severity and demyelination compared to vehicle treatment. Compared to vehicle treatment, late therapeutic BTK inhibition resulted in fewer spinal cord-infiltrating myeloid cells, with lower expression of CD86, pro-IL-1β, CD206, and Iba1, and higher expression of Arg1, in both tissue-resident and infiltrating myeloid cells, suggesting a less inflammatory myeloid cell milieu. These changes were accompanied by decreased spinal cord axonal damage. We show similar efficacy with two small molecule inhibitors, including a novel, highly selective, central nervous system-penetrant BTK inhibitor, GB7208. These results suggest that through lymphoid and myeloid cell regulation, BTK inhibition reduced neurodegeneration and disease progression during secondary progressive EAE.

Decreased melanoma CSF-1 secretion by Cannabigerol treatment reprograms regulatory myeloid cells and reduces tumor progression

ABSTRACT During solid tumor progression, the tumor microenvironment (TME) evolves into a highly immunosuppressive milieu. Key players in the immunosuppressive environment are regulatory myeloid cells, including myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), which are recruited and activated via tumor-secreted cytokines such as colony-stimulating factor 1 (CSF-1). Therefore, the depletion of tumor-secreted cytokines is a leading anticancer strategy. Here, we found that CSF-1 secretion by melanoma cells is decreased following treatment with Cannabis extracts. Cannabigerol (CBG) was identified as the bioactive cannabinoid responsible for the effects. Conditioned media from cells treated with pure CBG or the high-CBG extract reduced the expansion and macrophage transition of the monocytic-MDSC subpopulation. Treated MO-MDSCs also expressed lower levels of iNOS, leading to restored CD8+ T-cell activation. Tumor-bearing mice treated with CBG presented reduced tumor progression, lower TAM frequencies and reduced TAM/M1 ratio. A combination of CBG and αPD-L1 was more effective in reducing tumor progression, enhancing survival and increasing the infiltration of activated cytotoxic T-cells than each treatment separately. We show a novel mechanism for CBG in modulating the TME and enhancing immune checkpoint blockade therapy, underlining its promising therapeutic potential for the treatment of a variety of tumors with elevated CSF-1 expression.

Prognostic values of circulating TREM2+ and ARG1+ Mreg cells in adults with treatment‐naïve diffuse large B‐cell lymphoma

Introduction: Novel Trem2+ (triggering receptor expressed on myeloid cells 2) and Arg1+ (arginase 1) regulatory myeloid cells (Mreg) that lead to the dysfunction of CD8+ T cells and facilitate tumor growth were recently discovered in a murine cancer model by Yonatan Katzenelenbogen et al. However, as the roles of Mreg cells have never been examined in human cancer patients, we aim to elucidate the clinical impact of circulating Mreg cells on patients with treatment-naive B-cell NHL, especially focusing on DLBCL. Methods: This prospective, observational study enrolled 102 adults with newly diagnosed and treatment-naïve B-cell NHL, including 62 DLBCL, 25 FL (4 grade 3B), 4 MCL, 4 MZL, 2 LPL, 2 BL, and 3 mature B-cell neoplasms, from December 2020 to November 2022. We obtained human circulating TREM2+ and ARG1+ Mreg cells from freshly isolated peripheral blood and calculated their percentages among CD45+ and CD15- cells by flow-cytometry analysis. Non-stain (NS) and fluorescence minus one (FMO) controls were used for gating positive levels of surface TREM2 and intracellular ARG1, respectively. Results: Among 102 patients with B-cell NHL, those with high-risk IPI had significantly higher percentages of circulating Mreg cells than patients with intermediate or low-risk IPI (5.46% vs. 1.71% vs. 0.63%, P H vs. L < 0.001, P H vs. I = 0.032, P I vs. L = 0.005); patients with aggressive subtypes (including grade-3B FL) had significantly higher percentages of circulating Mreg cells than patients with indolent subtypes (1.89% vs. 0.93%, P = 0.023). For 62 DLBCL patients, those with high IPI risk (9.18% vs. 1.25%, P < 0.001), bulky mass ≥ 7.5 cm (5.08% vs. 1.18%, P = 0.057), or DEL (5.13% vs. 1.21%, P = 0.036) had significantly higher percentages of circulating Mreg cells (Figures A–F). More importantly, DLBCL patients with circulating Mreg cells ≥4.5% had significantly worse PFS and OS than those with Mreg cells <4.5% after a median follow-up of 14 months (Figures G and H); when utilizing multivariate Cox regression analysis, “circulating Mreg cells ≥4.5%” remained an independent prognostic factor for both PFS and OS after adjusting for confounding factors, including age, sex, high-risk IPI, bulky mass ≥7.5 cm, BM involvement, non-GCB type, and DEL. The research was funded by: The research was funded by grants from: (1) the Taiwan Ministry of Science and Technology (MOST 111-2314-B-075-037), (2) Taipei Veterans General Hospital (V110B-012), (3) the Chong Hin Loon Memorial Cancer and Biotherapy Research Center, (4) the Melissa Lee Cancer Foundation, and (5) the Taiwan Clinical Oncology Research Foundation. Keywords: Aggressive B-cell non-Hodgkin lymphoma, Diagnostic and Prognostic Biomarkers No conflicts of interests pertinent to the abstract.

Regulation of myeloid cells and inflammation marks increased susceptibility in a genetic model of acute viral infection-induced tissue damage.

Abstract M.H2 k/bmice are identical to MA/My parent strain aside from a C57L-derived region within the MHC, which causes these mice to develop significant splenic tissue damage during acute murine cytomegalovirus (MCMV) infection. To understand how MCMV infection leads to the induction of tissue damage, we probed immunological differences between the M.H2 k/band MA/My mice over time. Using tissue imaging and flow cytometry, we observed increased infiltration of neutrophils to the marginal zones of the M.H2 k/bmice aligning with the appearance of necrosis at 2 days post infection (dpi). While TUNEL staining identified increased cell death within these clusters, apoptosis was reduced, suggesting an inflammatory death pathway in the M.H2 k/bneutrophils. In line with this hypothesis, multiplex ELISA identified increased IL-6 and TGF-β in the spleens of M.H2 k/bmice at this time. Intriguingly, depletion of neutrophils prior to infection did not alleviate M.H2 k/bhistopathology or inflammation. Seeing the differential regulation of neutrophils, we assessed the state of other myeloid populations in the spleen during acute MCMV infection. We observed significant loss of marginal zone and red pulp macrophages (MZMs, RPMs) beginning at 2dpi and worsening over time in the M.H2 k/bmice. Further exploration into how the loss of these populations may contribute to tissue damage identified buildup of toxic lipid peroxidation byproduct 4HNE early in the MZMs and progressing through the RPMs alongside the development of histopathology. In conclusion, we have identified increased inflammation, oxidative stress, and macrophage loss in M.H2 k/bspleens during acute MCMV infection that tracks with localization and temporal appearance of histopathology. NIH NIAID R01AI50072, Department of Medicine/Nephrology, Center for Immunity Inflammation and Regenerative Medicine, Beirne B Carter Center for Immunology Research.

Extracorporeal Photopheresis Suppresses Transplant Fibrosis by Inducing Decorin Expression in Alveolar Macrophages.

Extracorporeal Photopheresis Suppresses Transplant Fibrosis by Inducing Decorin Expression in Alveolar Macrophages.

Shegan Mahuang Decoction May Reduce Airway Inflammation in Neutrophilic Asthmatic Mice by Improving the Mitochondrial Function of Bronchoalveolar Lavage Fluid Exosomes.

Asthma is a common pulmonary disease mainly caused by the infiltration of neutrophils. There is a limit to the therapeutic effects of the available asthma drugs on neutrophilic asthma. Shegan Mahuang Decoction (SMD) is one of the representative traditional Chinese medicine (TCM) prescriptions for asthma, and it can effectively relieve the clinical symptoms of patients. However, the effect of SMD on the treatment of neutrophilic asthma remains unknown. In this study, a mouse model of neutrophilic asthma induced by lipopolysaccharide (LPS)/ovalbumin (OVA) was established, and the effect of a modified SMD prescription on the model was evaluated. After treatment, SMD was demonstrated to be therapeutically effective on asthmatic mice via airway resistance detection and lung pathology and was able to affect cytokine levels in vivo. Further experiments verified that SMD regulated the expression of mitochondrial function proteins in bronchoalveolar lavage fluid (BALF) exosomes. The results demonstrate that SMD confers a therapeutic effect on a neutrophilic asthma mouse model, and it may reduce neutrophil airway inflammation by regulating myeloid-derived regulatory cell (MDRC) function and airway exosome mitochondrial function.

Electroacupuncture regulates macrophage, neutrophil, and oral microbiota to alleviate alveolar bone loss and inflammation in experimental ligature-induced periodontitis.

Electroacupuncture (EA) regulates distant body physiology through somatic sensory autonomic reflexes, balances the microbiome, and can promote the release of immune cells into bloodstream, thereby inhibiting severe systemic inflammation. This makes it possible to use EA as an integrated treatment for periodontitis. In this study, EA was applied to the ST36 acupoints in a ligature-induced periodontitis (LIP) mouse model. Then the effects of EA on periodontal myeloid cells, cytokines, and the microbiome were comprehensively analysed using flow cytometry, quantitative Polymerase Chain Reaction (PCR), and 16 S sequencing. Results demonstrated that EA could significantly relieve periodontal bone resorption. EA also suppressed the infiltration of macrophages and neutrophils, reduced gene expression of the pro-inflammatory cytokines IL-1β, IL-6, IL-17 and TNF-α, and increased expression of the anti-inflammatory factors IL-4 and IL-10 in periodontal tissues. Moreover, composition of the periodontal microbiome was regulated by EA, finding that complex of microbiota, including supragingival Veillonella, subgingival Streptococcus, and subgingival Erysipelatoclostridium, were significantly reduced. Meanwhile, nitrate and nitrate-related activities of subgingival microbiota were reversed. Network analysis revealed close relationships among Veillonella, Streptococcus, and Bacteroides. Our study indicates that EA can effectively alleviate inflammation and bone resorption in LIP mice, potentially via the regulation of myeloid cells, cytokines, and periodontal microbiome.

The therapeutic potential of TREM2 in cancer

Cancer continues to be a substantial health concern and a leading cause of death in the United States and around the world. Therefore, it is important to continue to explore the potential of novel therapeutic targets and combinatorial therapies. Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane receptor of the immunoglobulin superfamily that associates with DNAX activation protein (DAP) 12 and DAP10 to propagate signals within the cell. TREM2 has primarily been recognized for its expression on cells in the monocyte-macrophage lineage, with the majority of work focusing on microglial function in Alzheimer’s Disease. However, expansion of TREM2 research into the field of cancer has revealed that epithelial tumor cells as well as intratumoral macrophages and myeloid regulatory cells also express TREM2. In this review, we discuss evidence that TREM2 contributes to tumor suppressing or oncogenic activity when expressed by epithelial tumor cells. In addition, we discuss the immunosuppressive role of TREM2-expressing intratumoral macrophages, and the therapeutic potential of targeting TREM2 in combination with immune checkpoint therapy. Overall, the literature reveals TREM2 could be considered a novel therapeutic target for certain types of cancer.

Oxygen Sensing in Innate Immune Cells: How Inflammation Broadens Classical Hypoxia-Inducible Factor Regulation in Myeloid Cells.

Significance: Oxygen deprivation (hypoxia) is a common feature at sites of inflammation. Immune cells and all other cells present at the inflamed site have to adapt to these conditions. They do so by stabilization and activation of hypoxia-inducible factor subunit α (HIF-1α and HIF-2α, respectively), enabling constant generation of adenosine triphosphate (ATP) under these austere conditions by the induction of, for example, glycolytic pathways. Recent Advances: During recent years, it has become evident that HIFs play a far more important role than initially believed because they shape the inflammatory phenotype of immune cells. They are indispensable for migration, phagocytosis, and the induction of inflammatory cytokines by innate immune cells and thereby enable a crosstalk between innate and adaptive immunity. In short, they ensure the survival and function of immune cells under critical conditions. Critical Issues: Up to now, there are still open questions regarding the individual roles of HIF-1 and HIF-2 for the different cell types. In particular, the loss of both HIF-1 and HIF-2 in myeloid cells led to unexpected and contradictory results in the mouse models analyzed so far. Similarly, the role of HIF-1 in dendritic cell maturation is unclear due to inconsistent results from in vitro experiments. Future Directions: The HIFs are indispensable for immune cell survival and action under inflammatory conditions, but they might also trigger over-activation of immune cells. Therefore, they might be excellent setscrews to adjust the inflammatory response by pharmaceuticals. China and Japan and very recently (August 2021) Europe have approved prolyl hydroxylase inhibitors (PHIs) to stabilize HIF such as roxadustat for clinical use to treat anemia by increasing the production of erythropoietin, the classical HIF target gene. Nonetheless, we need further work regarding the use of PHIs under inflammatory conditions, because HIFs show specific activation and distinct expression patterns in innate immune cells. The extent to which HIF-1 or HIF-2 as a transcription factor regulates the adaptation of immune cells to inflammatory hypoxia differs not only by the cell type but also with the inflammatory challenge and the surrounding tissue. Therefore, we urgently need isoform- and cell type-specific modulators of the HIF pathway. Antioxid. Redox Signal. 37, 956-971.

Cross-talk between HIF and PD-1/PD-L1 pathways in carcinogenesis and therapy.

Tumor-associated hypoxia plays an important role in carcinogenesis and metastasis. The expression, activation, and stabilization of hypoxia-inducible transcription factors (HIFs) support malignant cell survival, proliferation, plasticity, and motility. Hypoxia also upregulates the expression of programmed cell death ligand 1 (PD-L1) in malignant and immune regulatory cells. Therefore, the combination of HIF inhibitors and checkpoint inhibitors (CPIs) is promising for boosting antitumor immunity and diminishing malignant cell plasticity and therapy resistance. In this issue of the JCI, Salman et al. report the development of a specific agent that inhibited HIF-1/2–mediated gene expression in tumor cells and suppressed tumor growth. Bailey, Liu, et al. in this issue demonstrate that targeting HIF-1α abrogated PD-L1–mediated immune evasion by suppressing PD-L1 expression on malignant and myeloid regulatory cells, causing tumor rejection. These findings suggest that targeting the HIF/PD-L1 axis with specific HIF inhibitors should improve the safety and efficacy of CPIs for cancer therapy.

Conditioning of maternal monocytes to myeloid regulatory cells by endometrial stromal cells

Conditioning of maternal monocytes to myeloid regulatory cells by endometrial stromal cells

Nitrogen-Doped Carbon Nanotube Cups for Cancer Therapy.

Carbon nanomaterials have attracted significant attention for a variety of biomedical applications including sensing and detection, photothermal therapy, and delivery of therapeutic cargo. The ease of chemical functionalization, tunable length scales and morphologies, and ability to undergo complete enzymatic degradation make carbon nanomaterials an ideal drug delivery system. Much work has been done to synthesize carbon nanomaterials ranging from carbon dots, graphene, and carbon nanotubes to carbon nanocapsules, specifically carbon nanohorns or nitrogen-doped carbon nanocups. Here, we analyze specific properties of nitrogen-doped carbon nanotube cups which have been designed and utilized as drug delivery systems with the focus on the loading of these nanocapsules with specific therapeutic cargo and the targeted delivery for cancer therapy. We also summarize our targeted synthesis of gold nanoparticles on the open edge of nitrogen-doped carbon nanotube cups to create loaded and sealed nanocarriers for the delivery of chemotherapeutic agents to myeloid regulatory cells responsible for the immunosuppressive properties of the tumor microenvironment and thus tumor immune escape.

A nonhuman primate model of vertical sleeve gastrectomy facilitates mechanistic and translational research in human obesity

SummaryThe obesity epidemic significantly contributes to overall morbidity and mortality. Bariatric surgery is the gold standard treatment for obesity and metabolic dysfunction, yet the mechanisms by which it exerts metabolic benefit remain unclear. Here, we demonstrate a model of vertical sleeve gastrectomy (VSG) in nonhuman primates (NHP) that mimics the complexity and outcomes in humans. We also show that VSG confers weight loss and durable metabolic benefit, where equivalent caloric intake in shams resulted in significant weight gain following surgery. Furthermore, we show that VSG is associated with early, weight-independent increases in bile acids, short-chain fatty acids, and reduced visceral adipose tissue (VAT) inflammation with a polarization of VAT-resident immunocytes toward highly regulatory myeloid cells and Tregs. These data demonstrate that this strongly translational NHP model can be used to interrogate factors driving successful intervention to unravel the interplay between physiologic systems and improve therapies for obesity and metabolic syndrome.

Genetic in situ engineering of myeloid regulatory cells controls inflammation in autoimmunity

The ability of myeloid regulatory cells (MRCs) to control immune responses and to promote tolerance has prompted enormous interest in exploiting them therapeutically to treat inflammation, autoimmunity, or to improve outcomes in transplantation. While immunomodulatory small-molecule compounds and antibodies have provided relief for some patients, the dosing entails high systemic drug exposures and thus increased risk of off-target adverse effects. More recently, MRC-based cell-therapy products have entered clinical testing for tolerance induction. However, the elaborate and expensive protocols currently required to manufacture engineered MRCs ex vivo put this approach beyond the reach of many patients who might benefit. A solution could be to directly program MRCs in vivo. Here we describe a targeted nanocarrier that delivers in vitro-transcribed mRNA encoding a key anti-inflammatory mediator. We demonstrate in models of systemic lupus erythematosus that infusions of nanoparticles formulated with mRNA encoding glucocorticoid-induced leucine zipper (GILZ) effectively control the disease. We further establish that these nanoreagents are safe for repeated dosing. Implemented in the clinic, this new therapy could enable physicians to treat autoimmune disease while avoiding systemic treatments that disrupt immune homeostasis.