Commentary
Abstract
Transplantation of allogeneic islets of Langerhans, which include the insulin-producing β cells of the endocrine pancreas, holds curative potential for type 1 diabetes (T1D). However, protecting the allograft from the host immune system has long been a challenge impeding wider use of this therapy. Inducing mixed hematopoietic chimerism via allogeneic hematopoietic stem cell transplantation (HSCT) can achieve long-lasting donor-specific immune tolerance, but the toxicities of conventional HSCT conditioning agents limit the use of this approach. In this issue of the JCI, Bhagchandani et al. have used the JAK1/2 inhibitor baricitinib to optimize a nonmyeloablative antibody-based HSCT conditioning regimen, achieving multilineage hematopoietic engraftment, which enabled curative islet allotransplantation in a mouse model of T1D.
Authors
Stephen P. Persaud, John F. DiPersio
Abstract
Chimeric antigen receptor T cell (CAR-T) therapy has transformed the treatment of hematologic malignancies, yet, severe inflammatory toxicities continue to limit its broader use. In this issue of the JCI, Goala et al. uncovered a mechanistic link between IFN-γ–driven inflammation and disrupted neutrophil homeostasis, revealing that cytokine release syndrome (CRS) and immune cell–associated hematologic toxicity (ICAHT) stem from a shared biological pathway. Using IL-2Ra–deficient mice and patient samples, they showed that IFN-γ suppressed IL-17A and granulocyte colony-stimulating factor (G-CSF), disrupting granulopoiesis and neutrophil survival. Strikingly, IFN-γ blockade eased both CRS and neutropenia without diminishing CAR-T efficacy, suggesting a path toward safer, better-tolerated cell therapies.
Authors
Stefanie R. Bailey, Marcela V. Maus
Abstract
Pancreatic cancer cells “live on the edge,” starved of nutrients, compressed by abundant stiff stroma, and deprived of oxygen. In this issue, Xu et al. leveraged human pancreas organoid–based CRISPR screens to identify new driver genes in pancreatic ductal adenocarcinoma (PDAC) development. Neurofibromatosis type 2 (NF2) emerged as the top tumor suppressor, whose loss enhances PDAC malignancy. Inactivation of NF2, which encodes the protein Merlin, promoted growth factor independence and enhanced macropinocytosis upon nutrient deprivation. Thus, NF2 status dictates the adaptability of pancreatic tumors under nutrient limitation, with NF2 inactivation endowing PDACs with the ability to survive the constraints of the harsh tumor microenvironment.
Authors
Sofia Ferreira, Laura D. Attardi
Abstract
Radiotherapy is a key treatment modality in many malignancies, but radiation-induced immunosuppression can undermine its outcomes and diminish the efficacy of combinatorial strategies, like radioimmunotherapy. In this issue of the JCI, Deng et al. implicate cGAS/STING signaling in the recruitment of γδ T cells that drive downstream radioresistance. Radiation-induced microparticles containing double-stranded tumor DNA led to activation of the cGAS/STING pathway in macrophages, promoting γδ T cell recruitment through CCL20 signaling. In mouse models, γδ T cell–dependent recruitment of myeloid-derived suppressor cells and T cell suppression curbed radiotherapy efficacy and drove antitumor immunity. Ablation of γδ T cells improved the efficacy of radiotherapy alone and radiotherapy combined with immune checkpoint inhibitors in mouse models, supporting further investigation of γδ T cell targeting to improve clinical outcomes with radioimmunotherapy. The findings also add complexity to the function of the cGAS/STING pathway in setting the balance between antitumor immunity and immunosuppression.
Authors
Brooke C. Braman, David R. Raleigh
Abstract
Chronic pain etiology involves a shared genetic profile, but its cellular context is poorly defined. In a study published in this issue of the JCI, Toikumo et al. integrated a chronic pain GWAS meta-analysis (n >1.2 million) with single-cell omics data from human brain and dorsal root ganglia. Genetic risk was predominantly enriched in central glutamatergic neurons, particularly those in the prefrontal cortex, hippocampus, and amygdala. In the periphery, the C-fiber nociceptor subtype hPEP.TRPV1/A1.2 was highlighted. Implicated genes converged on involvement in synaptic function and neuron projection development. This work identifies specific central and peripheral cell types that define the genetic architecture of chronic pain, providing a foundation for targeted translational research.
Authors
Erick J. Rodríguez-Palma, Rajesh Khanna
Abstract
Studies of amyloid-β (Aβ) in Alzheimer’s disease pathology have revealed the peptide’s complex roles in synaptic function. The study by Siddu et al. in this issue clarifies the contexts in which Aβ peptides may be synaptogenic or synaptotoxic. This commentary integrates the study’s major findings with the salient findings of others that, over recent years, have redefined Aβ from a troublesome waste product into a physiological agent of the innate immune response and a modulator of synaptic homeostasis. Convergent evidence demonstrates how free, nonaggregated Aβ supports synaptic structure and activity, whereas oligomeric assemblies enact an adaptive brake on excitatory drive that can become maladaptive with age and inflammation. This redefined perspective on Aβ function emphasizes an evolutionarily conserved feedback loop linking neuronal activity, amyloid generation, and synaptic tuning that protects energy balance under stress but, when dysregulated, promotes proteostatic failure, persistent neuroinflammation, and network dysfunction characteristic of Alzheimer’s disease.
Authors
Joachim Herz
Abstract
Approximately 80% of Merkel cell carcinoma (MCC) cases are caused by Merkel cell polyomavirus (MCV), driven by its T antigen oncogene. Why MCV drives MCC, a skin cancer that displays the neuroendocrine Merkel cell phenotype, remains unclear. In this issue of the JCI, Miao et al. demonstrated that MCC tumor survival requires neuroendocrine-lineage transcription factors, which are recruited to superenhancers (SEs) with the viral small T antigen oncoprotein to promote the neuroendocrine Merkel cell lineage of the cancer. Surprisingly, SEs mapped near the MCV integration site in MCC, and two SE-associated neuroendocrine transcription factors drove viral T antigen gene expression. MCV oncogene and neuroendocrine transcriptional network interactions rendered this viral tumorigenesis dependent on the Merkel cell lineage. Together with reports from other groups, the findings explain why MCV-associated cancer is specifically linked to the Merkel cell phenotype and identify epigenetic strategies targeting of lineage-dependent oncogene circuitry to treat virus-positive MCC.
Authors
Masahiro Shuda
Abstract
The aryl hydrocarbon receptor (AhR) is increasingly recognized as a physiologic modulator of the immune response, a function that extends beyond its established role as a sensor for environmental xenobiotics. In a recent report published in the JCI, Cros et al. demonstrate that the AhR restrains tonic, microbiota-driven inflammatory cytokine production in monocytes. Through the combined use of murine models, human ex vivo systems, and the analysis of patient-derived data, Cros and coworkers established that the AhR limits stimulator of IFN gene–induced (STING-induced) proinflammatory signals. These findings define cell type–specific physiologic roles for the AhR in the regulation of innate immunity and underscore its potential as a therapeutic target for the treatment of inflammatory and autoimmune diseases.
Authors
Jessica E. Kenison, Francisco J. Quintana
Abstract
Loss of circulating insulin resulting from autoimmune destruction of β cells is the defining characteristic of type 1 diabetes (T1D), but islet dysfunction in T1D affects both β cells and α cells. Advances in multiomic analyses and the systematic collection of diseased human pancreata are enabling new approaches for diabetes research; hypotheses can be generated from observations in the affected human tissue and then tested in human islets, stem cell–derived islets, or humanized mice. The study by dos Santos and colleagues that appears in this issue of the JCI is an excellent example of the advantages and challenges posed by this approach. Through integrated analyses that combined electrophysiological and transcriptomic profiling, the authors provided detailed insights into the mechanisms leading to α cell dysfunction in islets from individuals with T1D.
Authors
Decio L. Eizirik, Priscila L. Zimath
Abstract
Type 2 diabetes mellitus affects over 38 million Americans, with diabetic kidney disease as a major complication partly driven by lipotoxicity. Fatty acid transport protein 2 (FATP2) regulates uptake and activation of long-chain fatty acids, making it a therapeutic target in metabolic disease. In this issue of the JCI, Khan et al. investigated FATP2 in glycemic control. In db/db mice, global FATP2 deletion reduced plasma glucose via sustained insulin secretion, with expression restricted to pancreatic α cells. FATP2-deficient db/db mice also showed suppressed glucagon and reduced alanine-stimulated gluconeogenesis, implicating α cell FATP2 in systemic glucose regulation. The FATP2-specific inhibitor lipofermata enhanced α cell–derived glucagon-like peptide 1 (GLP-1) secretion, expanded GLP-1–positive α cell mass, and promoted paracrine insulin release — effects reversed by GLP-1 receptor antagonism. These findings identify FATP2 as a key regulator linking lipid handling to α cell hormone secretion and glucose control, positioning its inhibition as a potential complement to incretin-based therapies.
Authors
Paul N. Black, Concetta C. DiRusso
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