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Single-cell adaptive immune receptor repertoire sequencing (scAIRR-seq) and single-cell RNA sequencing (scRNA-seq) provide a transformative approach to profiling immune responses at unprecedented resolution across diverse pathophysiologic contexts. This work presents scRepertoire 2, a substantial update to our R package for analyzing and visualizing single-cell immune receptor data. This new version introduces an array of features designed to enhance both the depth and breadth of immune receptor analysis, including improved workflows for clonotype tracking, repertoire diversity metrics, and novel visualization modules that facilitate longitudinal and comparative studies. Additionally, scRepertoire 2 offers seamless integration with contemporary single-cell analysis frameworks like Seurat and SingleCellExperiment, allowing users to conduct end-to-end single-cell immune profiling with transcriptomic data. Performance optimizations in scRepertoire 2 resulted in a 85.1% increase in speed and a 91.9% reduction in memory usage from the first version over the range repertoire size tested in benchmarking, addressing the demands of the ever-increasing size and scale of single-cell studies. This release marks an advancement in single cell immunogenomics, equipping researchers with a robust toolset to uncover immune dynamics in health and disease.

The tumor microenvironment (TME) is composed of a diverse and dynamic spectrum of cell types, cellular activities, and cell–cell interactions (CCI). Understanding the complex CCI within the TME is critical for advancing cancer treatment strategies, including modulating or predicting drug responses. Recent advances in omics technologies, including spatial transcriptomics and proteomics, have allowed improved mapping of CCI within the TME. The integration of omics insights from different platforms may facilitate the identification of novel biomarkers and therapeutic targets. This review discusses the latest computational methods for inferring CCIs from different omics data and various CCI and drug databases, emphasizing their applications in predicting drug responses. We also comprehensively summarize recent patents, clinical trials, and publications that leverage these cellular interactions to refine cancer treatment approaches. We believe that the integration of these CCI-focused technologies can improve personalized therapy for cancer patients, thereby optimizing treatment outcomes and paving the way for next-generation precision oncology.

Nuclear hormone receptors have important roles in the regulation of metabolic and inflammatory pathways. The retinoid-related orphan receptor alpha (Rorα)-deficient staggerer (sg/sg) mice display several phenotypes indicative of aberrant lipid metabolism, including dyslipidemia, and increased susceptibility to atherosclerosis. In this study we demonstrate that macrophages from sg/sg mice have increased ability to accumulate lipids and accordingly exhibit larger lipid droplets (LD). We have previously shown that BMMs from sg/sg mice have significantly decreased expression of cholesterol 25-hydroxylase (Ch25h) mRNA, the enzyme that produces the oxysterol, 25-hydroxycholesterol (25HC), and now confirm this at the protein level. 25HC functions as an inverse agonist for RORα. siRNA knockdown of Ch25h in macrophages up-regulates Vldlr mRNA expression and causes increased accumulation of LDs. Treatment with physiological concentrations of 25HC in sg/sg macrophages restored lipid accumulation back to normal levels. Thus, 25HC and RORα signify a new pathway involved in the regulation of lipid homeostasis in macrophages, potentially via increased uptake of lipid which is suggested by mRNA expression changes in Vldlr and other related genes.

The central nervous system has historically been viewed as an immune-privileged site, but recent data have shown that the meninges—the membranes that surround the brain and spinal cord—contain a diverse population of immune cells 1 . So far, studies have focused on macrophages and T cells, but have not included a detailed analysis of meningeal humoral immunity. Here we show that, during homeostasis, the mouse and human meninges contain IgA-secreting plasma cells. These cells are positioned adjacent to dural venous sinuses: regions of slow blood flow with fenestrations that can potentially permit blood-borne pathogens to access the brain 2 . Peri-sinus IgA plasma cells increased with age and following a breach of the intestinal barrier. Conversely, they were scarce in germ-free mice, but their presence was restored by gut re-colonization. B cell receptor sequencing confirmed that meningeal IgA + cells originated in the intestine. Specific depletion of meningeal plasma cells or IgA deficiency resulted in reduced fungal entrapment in the peri-sinus region and increased spread into the brain following intravenous challenge, showing that meningeal IgA is essential for defending the central nervous system at this vulnerable venous barrier surface. IgA-secreting plasma cells that originate in the intestine are found in the meninges, where they protect the brain against pathogens.

While paediatric blood cancers are deadly, modern medical advances have enabled clinicians to measure levels of residual cancer cells to manage therapeutic strategies for patients. However, blood cancers, including leukaemias and lymphomas, are highly heterogeneous and is comprised of complex clonal populations that can hinder efforts in detecting the cancer cells as well as managing treatments. Furthermore, the tumour microenvironment is comprised of heterogenous immune dynamics that may be different between patients. High‐throughput sequencing has constributed to new discoveries in genetic and transcriptomic alterations underpinning cancer, including blood cancers, and has changed how patients are monitored and managed. Here we discuss the recent efforts using single‐cell approach, particularly on efforts to track clonal heterogenity of paediatric blood cancer and the underlying immune response, highlighting avenues for novel biomarker discovery that may have significant impact on clinical oncology practice.

Dysfunction of interleukin-10 producing regulatory B cells has been associated with the pathogenesis of autoimmune diseases, but whether regulatory B cells can be therapeutically induced in humans is currently unknown. Here we demonstrate that a subset of activated B cells expresses CD25, and the addition of low-dose recombinant IL-2 to in vitro stimulated peripheral blood and splenic human B cells augments IL-10 secretion. Administration of low dose IL-2, aldesleukin, to patients increases IL-10-producing B cells. Single-cell RNA sequencing of circulating immune cells isolated from low dose IL2-treated patients reveals an increase in plasmablast and plasma cell populations that are enriched for a regulatory B cell gene signature. The transcriptional repressor BACH2 is significantly down-regulated in plasma cells from IL-2-treated patients, BACH2 binds to the IL-10 gene promoter, and Bach2 depletion or genetic deficiency increases B cell IL-10, implicating BACH2 suppression as an important mechanism by which IL-2 may promote an immunoregulatory phenotype in B cells. The dysfunction of IL-10 secreting regulatory B cells has been linked to the pathogenesis of autoimmune disease. Here the authors show that low dose IL-2 therapy can enhance IL-10 production in regulatory B cell populations via the modulation of BACH2.

The generation of local immune responses in organs requires a coordinated effort, not just from immune cells, but also from ‘structural’ cells such as epithelial cells, endothelial cells and fibroblasts. New insights gained from profiling these cells across organs in the mouse emphasizes the important contribution of this structural cell network to organ immunity.

Single‐cell RNA sequencing (scRNA‐seq) is a powerful tool for investigating paediatric cancers, but individual studies often profile a small number of individuals. It is now the standard practice to upload the scRNA‐seq data to data repositories to support scientific reproducibility. Public data deposition is a cost‐effective and sustainability‐conscious solution that allows any researcher to download and analyse existing scRNA‐seq data to develop new ideas. This is incredibly valuable, especially in the context of paediatric cancer research, where access to funding and to patient cohorts may be prohibitive. However, standards for data deposition are absent, leading to significant issues that may slow progress. As a consequence, it is difficult, even impossible, for other researchers to validate findings or utilise these data for tailored analyses. Here, we systematically accessed and reviewed publicly available scRNA‐seq data sets from various paediatric cancer studies, covering over 1.3 million cells across 488 clinical samples. We highlight striking inconsistencies with study design and data availability across several levels, which hinder downstream analyses and data reproducibility. To address these challenges, we propose a recommendations framework to improve data deposition practices that promote more effective use of scRNA‐seq data sets deposited on public repositories and accelerate discoveries in paediatric cancer research and beyond. We urge data standards institutes and repositories, such as NCBI Gene Expression Omnibus (GEO) and European Genome‐Phenome Archive (EGA), to strictly enforce these standardised data practices.

Radiotherapy is a critical component of cancer care but can cause osteoporosis and pathological insufficiency fractures in surrounding and otherwise healthy bone. Presently, no effective countermeasure exists, and ionizing radiation-induced bone damage continues to be a substantial source of pain and morbidity. The purpose of this study was to investigate a small molecule aminopropyl carbazole named P7C3 as a novel radioprotective strategy. Our studies revealed that P7C3 repressed ionizing radiation (IR)-induced osteoclastic activity, inhibited adipogenesis, and promoted osteoblastogenesis and mineral deposition in vitro. We also demonstrated that rodents exposed to clinically equivalent hypofractionated levels of IR in vivo develop weakened, osteoporotic bone. However, the administration of P7C3 significantly inhibited osteoclastic activity, lipid formation and bone marrow adiposity and mitigated tissue loss such that bone maintained its area, architecture, and mechanical strength. Our findings revealed significant enhancement of cellular macromolecule metabolic processes, myeloid cell differentiation, and the proteins LRP-4, TAGLN, ILK, and Tollip, with downregulation of GDF-3, SH2B1, and CD200. These proteins are key in favoring osteoblast over adipogenic progenitor differentiation, cell matrix interactions, and shape and motility, facilitating inflammatory resolution, and suppressing osteoclastogenesis, potentially via Wnt/β-catenin signaling. A concern was whether P7C3 afforded similar protection to cancer cells. Preliminarily, and remarkably, at the same protective P7C3 dose, a significant reduction in triple-negative breast cancer and osteosarcoma cell metabolic activity was found in vitro. Together, these results indicate that P7C3 is a previously undiscovered key regulator of adipo-osteogenic progenitor lineage commitment and may serve as a novel multifunctional therapeutic strategy, leaving IR an effective clinical tool while diminishing the risk of adverse post-IR complications. Our data uncover a new approach for the prevention of radiation-induced bone damage, and further work is needed to investigate its ability to selectively drive cancer cell death.

Background Paediatric sarcomas, including rhabdomyosarcoma, Ewing sarcoma and osteosarcoma, represent a group of malignancies that significantly contribute to cancer‐related morbidity and mortality in children and young adults. These cancers share common challenges, including high rates of metastasis, recurrence or treatment resistance, leading to a 5‐year survival rate of approximately 20% for patients with advanced disease stages. Despite the critical need, therapeutic advancements have been limited over the past three decades. The advent of chimeric antigen receptor (CAR)‐based immunotherapies offers a promising avenue for novel treatments. However, CAR‐T cells have faced significant challenges and limited success in treating solid tumours due to issues such as poor tumour infiltration, immunosuppressive tumour microenvironments and off‐target effects. In contrast, the adaptation of CAR technology for natural killer (NK) cells has demonstrated potential in both haematological and solid tumours, suggesting a new therapeutic strategy for paediatric sarcomas. Methods This study developed and validated a novel CAR‐NK cell therapy targeting the ephrin type‐A receptor‐2 (EphA2) antigen, which is highly expressed in various paediatric sarcomas. Results CAR expression was successfully detected on the surface of NK cells post‐electroporation, indicating successful transfection. Significantly, EphA2‐specific CAR‐NK cells demonstrated enhanced cytotoxic activity against several paediatric sarcoma cell lines in vitro, including those of rhabdomyosarcoma, Ewing sarcoma and osteosarcoma, compared to unmodified NK cells. Transient messenger RNA (mRNA) transfection of NK cells is a safe approach in genetic engineering, with further chemical modifications to mRNA enhancing stability of temporal EphA2‐CAR expression in NK cells, thereby promoting prolonged protein expression. Additionally, in vivo EphA2‐CAR‐NK cells showed promising anti‐cancer activity in rhabdomyosarcoma and osteosarcoma mouse models. Conclusions The study provides a foundational basis for the clinical evaluation of EphA2‐targeted CAR‐NK cell therapy across a spectrum of paediatric sarcomas. The enhanced anti‐tumour effects observed in vitro/vivo suggests potential for improved therapeutic outcomes in hard‐to‐cure paediatric sarcomas. Key points Addressing unmet clinical needs in paediatric Sarcomas. Paediatric sarcomas, including rhabdomyosarcoma, Ewing sarcoma, and osteosarcoma, exhibit poor survival rates in advanced disease stages. The lack of significant therapeutic progress over the past three decades necessitates innovative treatment approaches. Advancing immunotherapy with CAR‐NK cells. Natural killer (NK) cells modified with chimeric antigen receptors (CARs) represent a promising strategy to overcome the limitations of CAR‐T cells, particularly in solid tumours. CAR‐NK cells are associated with enhanced tumour targeting, reduced off‐target effects, and improved safety profiles. EphA2 as a therapeutic target. EphA2, a receptor overexpressed in multiple paediatric sarcomas, is identified as a viable target for CAR‐based immunotherapy due to its critical role in tumour progression and angiogenesis. Innovations in mRNA‐based engineering. This study demonstrates the feasibility of transient mRNA transfection to engineer NK cells for CAR expression, offering a non‐integrative and safer alternative to viral transduction. Enhancements in mRNA stability through chemical modifications, can further optimise protein expression. Preclinical efficacy of EphA2‐CAR NK cells. EphA2‐specific CAR‐NK cells exhibit superior cytotoxicity against sarcoma cell lines in vitro and demonstrate significant anti‐tumour activity in in vivo mouse models of rhabdomyosarcoma and osteosarcoma. Clinical translation potential. The findings establish a strong preclinical rationale for the clinical evaluation of EphA2‐targeted CAR‐NK therapy as a novel immunotherapeutic option for paediatric sarcomas. Future research directions: Combining EphA2‐CAR NK cells with immune checkpoint inhibitors or other immunomodulatory agents could further enhance therapeutic outcomes and durability. Advanced preclinical models mimicking human tumour microenvironments are needed to refine and optimise this therapeutic approach. Human NK cells can be efficiently transfected with mRNA to safely express an EphA2‐CAR without genomic alterations. EphA2‐targeted CAR‐NK cells exhibit enhanced cytotoxicity against paediatric sarcomas, including rhabdomyosarcoma, Ewing sarcoma and osteosarcoma. This study demonstrate the potential of CAR‐NK cell therapies to improve outcomes in hard‐to‐cure paediatric sarcomas and provides a foundation for their clinical evaluation.