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Myelodysplastic syndromes (MDS) are age-dependent stem cell malignancies that share biological features of activated adaptive immune response and ineffective hematopoiesis. Here we report that myeloid-derived suppressor cells (MDSC), which are classically linked to immunosuppression, inflammation, and cancer, were markedly expanded in the bone marrow of MDS patients and played a pathogenetic role in the development of ineffective hematopoiesis. These clonally distinct MDSC overproduce hematopoietic suppressive cytokines and function as potent apoptotic effectors targeting autologous hematopoietic progenitors. Using multiple transfected cell models, we found that MDSC expansion is driven by the interaction of the proinflammatory molecule S100A9 with CD33. These 2 proteins formed a functional ligand/receptor pair that recruited components to CD33’s immunoreceptor tyrosine-based inhibition motif (ITIM), inducing secretion of the suppressive cytokines IL-10 and TGF-β by immature myeloid cells. S100A9 transgenic mice displayed bone marrow accumulation of MDSC accompanied by development of progressive multilineage cytopenias and cytological dysplasia. Importantly, early forced maturation of MDSC by either all-trans-retinoic acid treatment or active immunoreceptor tyrosine-based activation motif–bearing (ITAM-bearing) adapter protein (DAP12) interruption of CD33 signaling rescued the hematologic phenotype. These findings indicate that primary bone marrow expansion of MDSC driven by the S100A9/CD33 pathway perturbs hematopoiesis and contributes to the development of MDS.

Transforming growth factor β1 (TGF-β), enriched in the tumor microenvironment and broadly immunosuppressive, inhibits natural killer (NK) cell function by yet-unknown mechanisms. Here we show that TGF-β—treated human NK cells exhibit reduced tumor cytolysis and abrogated perforin polarization to the immune synapse. This result was accompanied by loss of surface expression of activating killer lg-like receptor 2DS4 and NKp44, despite intact cytoplasmic stores of these receptors. Instead, TGF-β depleted DNAX activating protein 12 kDa (DAP12), which is critical for surface NK receptor stabilization and downstream signal transduction. Mechanistic analysis revealed that TGF-β induced microRNA (miR)-183 to repress DAP12 transcription/translation. This pathway was confirmed with luciferase reporter constructs bearing the DAP12 3' untranslated region as well as in human NK cells by use of sense and antisense miR-183. Moreover, we documented reduced DAP12 expression in tumor-associated NK cells in lung cancer patients, illustrating this pathway to be consistently perturbed in the human tumor microenvironment.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by dysregulated and chronic systemic inflammatory responses that affect the synovium, bone, and cartilage causing damage to extra-articular tissue. Innate immunity is the first line of defense against invading pathogens and assists in the initiation of adaptive immune responses. Polymorphonuclear cells (PMNs), which include neutrophils, are the largest population of white blood cells in peripheral blood and functionally produce their inflammatory effect through phagocytosis, cytokine production and natural killer-like cytotoxic activity. TREM1 (triggering receptor expressed by myeloid cells) is an inflammatory receptor in PMNs that signals through the use of the intracellular activating adaptor DAP12 to induce downstream signaling. After TREM crosslinking, DAP12's tyrosines in its ITAM motif get phosphorylated inducing the recruitment of Syk tyrosine kinases and eventual activation of PI3 kinases and ERK signaling pathways. While both TREM1 and DAP12 have been shown to be important activators of RA pathogenesis, their activity in PMNs or the importance of DAP12 as a possible therapeutic target have not been shown. Here we corroborate, using primary RA specimens, that isolated PMNs have an increased proportion of both TREM1 and DAP12 compared to normal healthy control isolated PMNs both at the protein and gene expression levels. This increased expression is highly functional with increased activation of ERK and MAPKs, secretion of IL-8 and RANTES and cytotoxicity of target cells. Importantly, based on our hypothesis of an imbalance of activating and inhibitory signaling in the pathogenesis of RA we demonstrate that inhibition of the DAP12 signaling pathway inactivates these important inflammatory cells.

NK cell migration and activation are crucial elements of tumor immune surveillance. In mammary carcinomas, the number and function of NK cells is diminished, despite being positively associated with clinical outcome. MicroRNA-155 (miR-155) has been shown to be an important regulator of NK cell activation through its interaction with SHIP-1 downstream of inhibitory NK receptor signaling, but has not been explored in regard to NK cell migration. Here, we explored the migratory potential and function of NK cells in subcutaneous AT3 in mice lacking miR-155. Without tumor, these bic/miR-155-/- mice possess similar numbers of NK cells that exhibit comparable surface levels of cytotoxic receptors as NK cells from wild-type (WT) mice. Isolated miR-155-/- NK cells also exhibit equivalent cytotoxicity towards tumor targets in vitro compared to isolated WT control NK cells, despite overexpression of known miR-155 gene targets. NK cells isolated from miR-155-/- mice exhibit impaired F-actin polymerization and migratory capacity in Boyden-chamber assays in response chemokine (C-C motif) ligand 2 (CCL2). This migratory capacity could be normalized in the presence of SHIP-1 inhibitors. Of note, miR-155-/- mice challenged with mammary carcinomas exhibited heightened tumor burden which correlated with a lower number of tumor-infiltrating NK1.1+ cells. Our results support a novel, physiological role for SHIP-1 in the control of NK cell tumor trafficking, and implicate miR-155 in the regulation of NK cell chemotaxis, in the context of mammary carcinoma. This may implicate dysfunctional NK cells in the lack of tumor clearance in mice.

Abstract Background Intravenous (IV) nemvaleukin alfa (nemvaleukin, ALKS 4230) administered daily on days 1-5 in 21‑day cycles demonstrated antitumor activity and manageable safety in heavily pretreated advanced solid tumors. We present results from cohort 2 of the open-label phase I/II ARTISTRY-3 (NCT04592653) study, which evaluated less frequent IV dosing of nemvaleukin in advanced solid tumors. Methods Eligible patients received escalating IV nemvaleukin doses in 21-day cycles on 3 schedules: day 1, days 1 and 8, and days 1 and 4. The primary endpoint was the incidence of dose-limiting toxicities (DLTs). Results From April 2022 to June 2024, 52 patients received nemvaleukin. No DLTs were reported. Most treatment-related adverse events (TRAEs) were grade 1-2. Six patients (12%) experienced grade 3 TRAEs, the most common being neutropenia. Nemvaleukin exposure increased with escalating doses. Natural killer (NK) cell and CD8+ T-cell expansion in whole blood was observed, with minimal regulatory T-cell expansion. Nemvaleukin at 30 μg/kg on days 1 and 8 was the recommended phase II dose. No objective responses were observed; 16 (31%) patients had stable disease (6 [12%] for ≥3 months). Increased tumor microenvironment infiltration of NK cells and CD8+ T-cells was observed in on-treatment biopsies. Conclusions Less frequent IV doses of nemvaleukin demonstrated pharmacodynamic proof of mechanism and were tolerable with some disease stabilization.

Myeloid-derived suppressor cells (MDSCs) constitute a key checkpoint that impedes tumor immunity against cancer. Chemotherapeutic intervention of MDSCs has gained ground as a strategy for cancer therapy but its mechanism remains obscure.We report here a unique mechanism by which monocytic (M)-MDSCs are spared, allowing them to polarize towards M1 macrophages for reactivation of immunity against breast cancer. We first demonstrated that curcumin, like docetaxel (DTX), can selectively target CD11b + Ly6G + Ly6C low granulocytic (G)-MDSCs, sparing CD11b + Ly6G − Ly6C high M-MDSCs, with reduced tumor burden in 4T1-Neu tumor-bearing mice. Curcumin treatment polarized surviving M-MDSCs toward CCR7 + Dectin-1 − M1 cells, accompanied by IFN-γ production and cytolytic function in T cells. Selective M-MDSC chemoresistence to curcumin and DTX was mediated by secretory/cytoplasmic clusterin (sCLU). sCLU functions by trapping Bax from mitochondrial translocation, preventing the apoptotic cascade. Importantly, sCLU was only found in M-MDSCs but not in G-MDSCs. Knockdown of sCLU in M-MDSCs and RAW264.7 macrophages was found to reverse their natural chemoresistance. Clinically, breast cancer patients possess sCLU expression only in mature CD68 + macrophages but not in immature CD33 + immunosuppressive myeloid cells infiltrating the tumors. We thus made the seminal discovery that sCLU expression in M-MDSCs accounts for positive immunomodulation by chemotherapeutic agents.

Transforming growth factor β1 (TGF-β), enriched in the tumor microenvironment and broadly immunosuppressive, inhibits natural killer (NK) cell function by yet-unknown mechanisms. Here we show that TGF-β-treated human NK cells exhibit reduced tumor cytolysis and abrogated perforin polarization to the immune synapse. This result was accompanied by loss of surface expression of activating killer Ig-like receptor 2DS4 and NKp44, despite intact cytoplasmic stores of these receptors. Instead, TGF-β depleted DNAX activating protein 12 kDa (DAP12), which is critical for surface NK receptor stabilization and downstream signal transduction. Mechanistic analysis revealed that TGF-β induced microRNA (miR)-183 to repress DAP12 transcription/translation. This pathway was confirmed with luciferase reporter constructs bearing the DAP12 3' untranslated region as well as in human NK cells by use of sense and antisense miR-183. Moreover, we documented reduced DAP12 expression in tumor-associated NK cells in lung cancer patients, illustrating this pathway to be consistently perturbed in the human tumor microenvironment. [PUBLICATION ABSTRACT]

Endoscopic ultrasound-directed transgastric endoscopic retrograde cholangiopancreatography (EDGE) and endoscopic ultrasound-directed transenteric endoscopic retrograde cholangiopancreatography (EDEE) are innovative endoscopic techniques developed to overcome the challenges of biliary access in patients with surgically altered gastrointestinal anatomy. EDGE facilitates the creation of a gastro-gastric anastomosis, enabling endoscopic access to the excluded stomach and subsequent duodenum for endoscopic retrograde cholangiopancreatography (ERCP) procedures. Similarly, EDEE involves creating a gastro-jejunal anastomosis, allowing endoscopic access to the jejunum and hepaticojejunostomy for ERCP. These procedures are primarily indicated for patients with Roux-en-Y gastric bypass or other complex gastrointestinal surgeries that render traditional ERCP unfeasible. The major advantages of EDGE and EDEE include minimally invasive access to the biliary system, reduced procedural morbidity, and the ability to perform complex biliary interventions without additional surgeries. Using lumen-apposing metal stents in these procedures has further improved their safety and efficacy. This comprehensive review delves into EDGE and EDEE’s technical nuances, clinical outcomes, and safety profiles. Our extensive literature searches reveal high procedural success rates and low complication incidences, establishing these methods as viable alternatives to traditional surgical and percutaneous approaches. We also discuss recent technological advancements, including developing enhanced stents and endoscopic ultrasound-guided instruments, which have refined these techniques and expanded their applications. Moreover, the review examines the integration of EDGE and EDEE with other therapeutic modalities, such as cholangioscopy and intraductal lithotripsy, to optimize treatment outcomes. Future directions emphasize the need for larger, multicenter trials to validate these findings further and create standardized protocols to ensure consistent procedural efficacy and safety. This review highlights the transformative potential of EDGE and EDEE in therapeutic endoscopy, advocating for their broader adoption in clinical practice and ongoing innovation in this rapidly evolving field. Plain language summary New endoscopic techniques (EDGE and EDEE) for management of bile duct and pancreatic problems in patients with surgically changed anatomy Some patients who need treatment for bile duct or pancreatic problems have had surgeries that change the shape and connections in their digestive system. These changes make it difficult for doctors to reach the bile ducts using standard endoscopic procedures. Two new methods—called EDGE (Endoscopic Ultrasound Directed Transgastric ERCP) and EDEE (Endoscopic Ultrasound Directed Transenteric ERCP)—offer a solution. They allow doctors to create a new passage between parts of the digestive system using a special stent. This passage gives doctors access to the bile ducts with standard endoscopes, avoiding the need for open surgery. These techniques are especially useful for patients who have had a Roux-en-Y gastric bypass or other complex surgeries, where the standard route to the bile ducts is blocked. EDGE and EDEE are minimally invasive, meaning they involve less risk and shorter recovery times compared to surgery. This review article explains how these techniques work, their advantages, and how safe and effective they are. Studies show they have a high success rate and fewer complications than traditional surgical methods. They can also be used for repeated treatments if needed. The review also looks at new improvements in technology, such as better stents and instruments, and how these techniques can be combined with other treatments to improve results. Finally, the authors highlight the need for larger studies to confirm these promising results and support the use of EDGE and EDEE in routine medical practice.

Fish pectoral fins move in complex ways, acting as control surfaces to affect force balance during swimming and maneuvering. Though objectively less dynamic than their actinopterygian relatives, shark pectoral fins undergo complex conformational changes and movements during maneuvering. Asynchronous pectoral fin movement is documented during yaw turning in at least two shark species but the three-dimensional (3D) rotation of the fin about the body axes is unknown. We quantify the 3D actuation of the pectoral fin base relative to the body axes. We hypothesized that Pacific spiny dogfish rotate pectoral fins with three degrees of freedom relative to the body during volitional turning. The pectoral fin on the inside of the turn is consistently protracted, supinated, and depressed. Additionally, turning angular velocity increased with increasing fin rotation. Estimated drag on the fin increased and the shark decelerated during turning. Based on these findings, we propose that Pacific spiny dogfish uses drag-based turning during volitional swimming. Post-mortem muscle stimulation revealed depression, protraction, and supination of the pectoral fin through stimulation of the ventral and cranial pterygoideus muscles. These data confirm functional hypotheses about pectoral fin musculature and suggest that Pacific spiny dogfish actively rotate pectoral fins to facilitate drag-based turning.