Journal of Clinical Investigation最新文献

A major unmet need in estrogen receptor-positive (ER+) breast cancer is understanding the mechanisms that underlie resistance to endocrine therapy. Although accumulating evidence suggests an association between the tumor immune microenvironment (TIME) and endocrine response, the specific role of the TIME in mediating endocrine resistance remains unclear. In this issue of the JCI, Napolitano et al. analyzed tumor biopsies from patients with ER+ breast cancer and reported that endocrine-resistant tumors exhibited heightened CD8+ T cell infiltration and activation of the CXCL11 - CXCR3/-7 axis. Spatial and coculture analyses of these tumors demonstrated that the CD8+ T cell-associated chemokine CXCL11 drove estrogen-independent tumor growth. These findings identify an immune-mediated mechanism of endocrine resistance in breast cancer and identify CXCL11 as a potential biomarker and therapeutic vulnerability.

SCN8A encodes the voltage-gated sodium channel Nav1.6, which plays a key role in facilitating neuronal excitability. Mutations in SCN8A, particularly gain-of-function variants, cause SCN8A developmental and epileptic encephalopathy (DEE), a severe epilepsy syndrome characterized by seizures, cognitive dysfunction, movement disorders, and sudden unexpected death in epilepsy (SUDEP). The recurrent SCN8A variant R1872W impairs channel inactivation, causing neuronal hyperexcitability and seizures. Current treatments, including antiseizure medications, are often ineffective for patients with SCN8A DEE, highlighting the need for targeted therapies. We employed base editing to correct the R1872W SCN8A variant. An adenine base editor and guide RNA (SCN8A-ABE) were packaged within dual PhP.eB-adeno-associated viruses (AAVs) and administered to R1872W mice at P2. SCN8A-ABE significantly increased survival of mice expressing R1872W and either reduced seizure incidence and severity or eliminated seizure occurrence. Electrophysiological recordings revealed a rescue of seizure-associated neuronal hyperexcitability and suppression of the pathogenic persistent sodium current (INaP) in treated mice. Comorbidities, including diminished mobility and anxiety-like behaviors, were improved by SCN8A-ABE. These effects were achieved by a 32% absolute reduction in mutant transcripts, accompanied by conversion to SCN8A WT transcripts. Our findings demonstrate base editing as an effective targeted therapeutic approach for SCN8A DEEs by addressing the underlying genetic cause.

Circulating tumor DNA detection in renal cell carcinoma has long been limited by the disease's low DNA shedding. An aggressive subtype termed translocation renal cell carcinoma (tRCC) is notably more difficult to detect than the common type, clear-cell RCC, in part due to interindividual variability of gene fusions of the transcription factor TFE3, the driving factor in tRCC. In this issue of the JCI, Garinet et al. reported on an epigenomic liquid biopsy approach that identified a TFE3 fusion-associated chromatin signature specific to tRCC. This work demonstrated that fusion-driven epigenomic alterations can be captured noninvasively and used to distinguish tRCC from other renal cancer subtypes. Beyond its diagnostic potential, the approach described by Garinet et al. may enable disease monitoring and subtype classification in other genetically quiet tumors. Epigenomic liquid biopsy is a promising framework to improve diagnostic accuracy and guide personalized management for tRCC.

Cells release extracellular vesicles (EVs) with cargo that originates from distinct subcellular compartments, including the nucleus, cytoplasm, and plasma membrane. Given their diverse cargo, EVs play multiple roles in physiology and pathology, including in immune dysregulation and autoimmune pathogenesis. For example, EVs can act as autoantigens by transporting immunogenic molecules from the nucleus or cytoplasm, whereas EVs carrying membrane-bound MHCs from antigen-presenting cells can activate adaptive immunity by presenting self-antigens to T cells. EV-associated cytoplasmic peptidases or proteasomes contribute to immune regulation by modulating antigen processing and presentation. Moreover, EVs also drive inflammatory responses by shuttling a variety of proinflammatory molecules that sustain autoimmune responses. Intriguingly, emerging evidence indicates that EVs might contribute to autoimmune surveillance by activating cytosolic surveillance sensors, modulating immune checkpoints, regulating NK/T cell cytotoxicity, and altering macrophage and DC phagocytosis, representing an exciting and underexplored frontier in autoimmune research. By tackling critical knowledge gaps, this Review explores the emerging roles of EVs and their diverse cargo in driving autoimmune diseases, suggesting new perspectives on their potential as innovative therapeutic targets.

CRISPR/Cas9 base editing holds the potential to treat disease caused by single-nucleotide variants. In contrast with conventional CRISPR/Cas9 approaches, base editing enzymatically induces precise DNA alterations and can directly correct disease-causing variants. In this issue of JCI, Reever et al. used base editing to treat a mouse model of a severe neurodevelopmental disorder caused by a pathogenic missense variant in the voltage-gated sodium channel gene SCN8A. This work represents a starting point for the further refinement of base editing to treat genetic epilepsy.

Traditional polysaccharide vaccines are constrained by streptococcus pneumoniae diversity. We propose a protein-based pneumococcal vaccine (PBPV) - formulated with conserved surface proteins P3296, P5668, PRx1, and pneumolysin (Ply) - that could potentially offer superior immune breadth independent of capsular polysaccharide serotypes. Here, we evaluated the multifunctional antibody responses induced by PBPV, including immunogenicity, Ply neutralization, opsonophagocytic activity (OPA), and such nonopsonic functions as NK cell activation (ADNKA), antibody-dependent cellular phagocytosis, and neutrophil phagocytosis (ADNP) in a cohort of 50- to 69-year-olds. While PBPV showed shorter-lasting immune responses, including reduced Ply-neutralizing capacity, it provided broader cross-serotype protection than 23-valent pneumococcal polysaccharide vaccine. Correlation analysis identified distinct PspA-specific IgG subclass roles: P3296-IgG1 correlated with OPA, and IgG3 correlated with ADNKA/ADNP; P5668-IgG2 correlated with ADNKA/ADNP, and IgG3 correlated with OPA; and PRx1-IgG2 correlated with OPA, and IgG3 correlated with ADNKA. Critically, while no efficacy data have yet confirmed the protective effect of PBPV, its targeting of conserved proteins rather than capsular polysaccharides enables simplified manufacturing and expanded coverage, positioning it as a promising alternative to traditional multipolysaccharide vaccines.

The retinoid chromophore 11-cis-retinal triggers an intracellular cascade known as phototransduction that converts light into electrochemical signals. Enzymatic regeneration of 11-cis-retinal sustains vision, prevents the buildup of toxic byproducts, and is supported largely by the retinal pigmented epithelium. Directly visualizing rapidly changing retinoid intermediates in patients with inherited retinal diseases (IRDs) could provide essential therapeutic insights. In this issue, Engfer et al. introduced a groundbreaking strategy using the mouse retina as a genetically malleable model for the mammalian eye. Using cell-specific expression of lecithin:retinol acyltransferase to trap mobile retinols, they mapped the availability of 11-cis- and all-trans-retinoids within different retinal compartments under normal and diseased conditions. Their findings elucidate retinoid distribution in the retina and highlight important differences between mouse and human Müller glia. Here, we contextualize these advances within decades of research defining the visual cycle and retinoid biology, outlining the profound implications for therapeutic development for IRDs.

Metastatic progression in aggressive breast cancer (BC) depends on a tightly controlled vesicular recycling network regulated by RAB11, a small guanosine triphosphate enzyme (GTPase). In a cohort of more than 1,000 patients with BC, we identified SH3BP5L as the most highly expressed guanine nucleotide exchange factor (GEF) for RAB11A. High SH3BP5L expression marked an advanced tumor stage, distant metastasis, and poor prognosis, with significant associations in human epidermal growth factor receptor 2-positive (HER2+) and triple-negative breast cancer (TNBC). Using Förster resonance energy transfer (FRET) sensors and artificial intelligence- (AI-assisted) microscopy, we showed that cargo delivery to the plasma membrane required SH3BP5L-dependent activation of RAB11A and assembly of a complex with the anterograde motor KIF5B. This trafficking governed key metastatic features of TNBC, including β1 integrin recycling and α3β1 integrin surface exposure. Inhibition of SH3BP5L or its GEF activity reduced cell spreading in zebrafish and lung metastasis in mouse models, revealing a previously unidentified driver of BC dissemination and a potential therapeutic vulnerability.

Metastatic hormone-sensitive prostate cancer (mHSPC) is a clinically and molecularly heterogeneous disease. Recent insights into the biology underlying disease presentation, volume of disease, and response to therapies are starting to point toward biomarkers to improve selection for intensified and deintensified treatment strategies. In addition, the therapeutic landscape is rapidly changing, with new biomarker-driven studies targeting genotype (e.g., BRCA or PTEN mutant) and phenotype (e.g., prostate-specific membrane antigen status) in development for mHSPC. A better understanding of tumor heterogeneity, clonal evolution, and metastatic homing in prostate cancer will hopefully inform future strategies for local and systemic disease control, personalized monitoring strategies, and improved patient outcomes.