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Cancer cells elude anti-tumour immunity through multiple mechanisms, including upregulated expression of ligands for inhibitory immune checkpoint receptors. Phagocytosis by macrophages plays a critical role in cancer control. Therapeutic blockade of signal regulatory protein (SIRP)-α, an inhibitory receptor on macrophages, or of its ligand CD47 expressed on tumour cells, improves tumour cell elimination in vitro and in vivo, suggesting that blockade of the SIRPα-CD47 checkpoint could be useful in treating human cancer. However, the pro-phagocytic receptor(s) responsible for tumour cell phagocytosis is(are) largely unknown. Here we find that macrophages are much more efficient at phagocytosis of haematopoietic tumour cells, compared with non-haematopoietic tumour cells, in response to SIRPα-CD47 blockade. Using a mouse lacking the signalling lymphocytic activation molecule (SLAM) family of homotypic haematopoietic cell-specific receptors, we determined that phagocytosis of haematopoietic tumour cells during SIRPα-CD47 blockade was strictly dependent on SLAM family receptors in vitro and in vivo. In both mouse and human cells, this function required a single SLAM family member, SLAMF7 (also known as CRACC, CS1, CD319), expressed on macrophages and tumour cell targets. In contrast to most SLAM receptor functions, SLAMF7-mediated phagocytosis was independent of signalling lymphocyte activation molecule-associated protein (SAP) adaptors. Instead, it depended on the ability of SLAMF7 to interact with integrin Mac-1 (refs 18, 19, 20) and utilize signals involving immunoreceptor tyrosine-based activation motifs. These findings elucidate the mechanism by which macrophages engulf and destroy haematopoietic tumour cells. They also reveal a novel SAP adaptor-independent function for a SLAM receptor. Lastly, they suggest that patients with tumours expressing SLAMF7 are more likely to respond to SIRPα-CD47 blockade therapy.

Summary: Type 1 diabetes (T1D) results from a complex interplay of genetic predisposition, immunological dysregulation, and environmental triggers, that culminate in the destruction of insulin‐secreting pancreatic β cells. This review provides a comprehensive examination of the multiple factors underpinning T1D pathogenesis, to elucidate key mechanisms and potential therapeutic targets. Beginning with an exploration of genetic risk factors, we dissect the roles of human leukocyte antigen (HLA) haplotypes and non‐HLA gene variants associated with T1D susceptibility. Mechanistic insights gleaned from the NOD mouse model provide valuable parallels to the human disease, particularly immunological intricacies underlying β cell–directed autoimmunity. Immunological drivers of T1D pathogenesis are examined, highlighting the pivotal contributions of both effector and regulatory T cells and the multiple functions of B cells and autoantibodies in β‐cell destruction. Furthermore, the impact of environmental risk factors, notably modulation of host immune development by the intestinal microbiome, is examined. Lastly, the review probes human longitudinal studies, unveiling the dynamic interplay between mucosal immunity, systemic antimicrobial antibody responses, and the trajectories of T1D development. Insights garnered from these interconnected factors pave the way for targeted interventions and the identification of biomarkers to enhance T1D management and prevention strategies. [ABSTRACT FROM AUTHOR]

Rapid onset obesity with hypoventilation, hypothalamic, and autonomic dysregulation (ROHHAD) syndrome in childhood is characterized by abrupt onset weight gain and dysautonomia with variable neuroendocrine involvement. In the absence of definitive disease-modifying therapies, the primary management strategy remains symptom control. This case report describes the first successful correction of obesity, dysautonomia, and metabolic derangement in a patient with ROHHAD following Roux-en-Y gastric bypass. Anthropometrics, metabolic profiling, and stool microbiome composition were assessed in a longitudinal fashion. In the 48-month period following surgery, the patient body mass index (BMI) reduced by 9.5 kg/m2 and metabolic status improved, evidenced in weaning of insulin, and improved glycated hemoglobin, lipid profile, and hepatic enzymes. Chronic diarrhea resolved after surgery and prior to significant weight loss. Evaluation of stool bacterial composition and biomass demonstrated shifts in absolute abundance and taxonomic composition in longitudinal samples following surgery. This case demonstrates the potential efficacy of bariatric surgery in correcting the metabolic disruption of ROHHAD syndrome, producing long-term changes in gut microbiome composition and biomass. [ABSTRACT FROM AUTHOR]

Immune-targeted therapies have efficacy for treatment of autoinflammatory diseases. For example, treatment with the T cell–specific anti-CD3 antibody teplizumab delayed disease onset in participants at high risk for type 1 diabetes (T1D) in the TrialNet 10 (TN-10) trial. However, heterogeneity in therapeutic responses in TN-10 and other immunotherapy trials identifies gaps in understanding disease progression and treatment responses. The intestinal microbiome is a potential source of biomarkers associated with future T1D diagnosis and responses to immunotherapy. We previously reported that antibody responses to gut commensal bacteria were associated with T1D diagnosis, suggesting that certain antimicrobial immune responses may help predict disease onset. Here, we investigated anticommensal antibody (ACAb) responses against a panel of taxonomically diverse intestinal bacteria species in sera from TN-10 participants before and after teplizumab or placebo treatment. We identified IgG2 responses to three species that were associated with time to T1D diagnosis and with teplizumab treatment responses that delayed disease onset. These antibody responses link human intestinal bacteria with T1D progression, adding predictive value to known T1D risk factors. ACAb analysis provides a new approach to elucidate heterogeneity in responses to immunotherapy and identify individuals who may benefit from teplizumab, recently approved by the U.S. Food and Drug Administration for delaying T1D onset. Editor's summary: The U.S. FDA recently approved the immune-targeted therapy teplizumab as the first disease-modifying therapy for delaying onset of type 1 diabetes (T1D) in at-risk individuals. Examining participant data from the TrialNet 10 trial that supported this decision, Xie et al. now report that IgG2 antibodies against three gut microbial commensals are associated with the teplizumab response and with time to T1D diagnosis. They also found evidence of these relationships in an independent clinical trial, suggesting that anticommensal immune responses may play a role in T1D progression and may additionally be useful to identify individuals who will benefit from treatment in this setting. —Catherine Charneski [ABSTRACT FROM AUTHOR]

Xenograft studies indicate that some solid tumors and leukemias are organized as cellular hierarchies sustained by cancer stem cells (CSCs). Despite the promise of the CSC model, its relevance in humans remains uncertain. Here we show that acute myeloid leukemia (AML) follows a CSC model on the basis of sorting multiple populations from each of 16 primary human AML samples and identifying which contain leukemia stem cells (LSCs) using a sensitive xenograft assay. Analysis of gene expression from all functionally validated populations yielded an LSC-specific signature. Similarly, a hematopoietic stem cell (HSC) gene signature was established. Bioinformatic analysis identified a core transcriptional program shared by LSCs and HSCs, revealing the molecular machinery underlying 'sternness' properties. Both stem cell programs were highly significant independent predictors of patient survival and were found in existing prognostic signatures. Thus, determinants of stemness influence the clinical outcome of AML, establishing that LSCs are clinically relevant and not artifacts of xenotransplantation., The CSC model posits that many cancers are organized hierarchically and sustained by a subpopulation of CSCs at the apex that have self-renewal capacity (1). Two lines of evidence establish [...]

Am J Physiol Lung Cell Mol Physiol 298: L45-L56, 2010. First published November 6, 2009; doi: 10.1152/ajplung.90550.2008.--Distal lung development occurs through coordinated induction of myofibroblasts, epithelial cells, and capillaries. Lunatic Fringe (Lfng) is a [[beta].sub.1-3] N-acetylglucosamine transferase that modifies Notch receptors to facilitate their activation by Delta-like (D111/4) ligands. Lfng is expressed in the distal lung during saccular development, and deletion of this gene impairs myofibroblast differentiation and alveogenesis in this context. A similar defect was observed in [Notch2.sup.[beta]geo/+] [Notch3.sup.[beta]-geo/[beta]-geo] compound mutant mice but not in [Notch2.sup.[beta]geo/+] or [Notch3.sup.[beta]-geo/[beta]-geo] single mutants. Finally, to directly test for the role of Notch signaling in myofibroblast differentiation in vivo, we used ROSA26-[rtTA.sup./+];[tetO-CRE.sup./+];RBPJ[[kappa].sup.flox/flox] inducible mutant mice to show that disruption of canonical Notch signaling during late embryonic development prevents induction of smooth muscle actin in mesenchymal cells of the distal lung. In sum, these results demonstrate that Lfng functions to enhance Notch signaling in myofibroblast precursor cells and thereby to coordinate differentiation and mobilization of myofibroblasts required for alveolar septation. alveolar development

Skeletal morbidities continue to cause acute and long-term burdens for B-ALL patients underscoring the need to identify the mechanisms underlying these processes and to develop effective therapies. Our recent findings demonstrated that B-ALL cells isolated at patient diagnosis can cause bone destruction and have identified the receptor activator of nuclear factor κ-B (RANK-RANKL) ligand axis as a critical effector of these effects. [ABSTRACT FROM AUTHOR]