The Journal of investigative dermatology最新文献

Atopic dermatitis is a chronic inflammatory skin disorder that affects over 200 million people worldwide. Although disease etiology is multifaceted, the immune checkpoint molecules OX40 and OX40L have a critical role in disease development. Recent clinical trials demonstrated that the OX40-targeting antibodies rocatinlimab (KHK4083/AMG-451) and telazorlimab (GBR-830/ISB-830), and the OX40L-targeting antibody amlitelimab (KY1005), significantly improve symptoms of atopic dermatitis. However, the epitopes where these antibodies bind OX40 and OX40L remain unclear, and therefore, so do the mechanisms by which they specifically disrupt OX40-OX40L signaling. To address this, computational modeling was performed to predict antibody-protein co-complexes, and their interaction interfaces were characterized. Binding free energy of specific OX40 or OX40L residue-residue interactions within 5 Å of the antibody binding interface were analyzed using MM-PBSA with a per-residue energy decomposition analysis. Our analysis suggests rocatinlimab and amlitelimab directly inhibit OX40-OX40L interactions by physically blocking the cognate OX40-OX40L interface via steric occlusion, whereas telazorlimab disrupts a critical OX40-OX40L bond. Together, this work provides molecular characterization of the epitopes of OX40 and OX40L targeted biologics emerging in dermatology.

Atopic dermatitis (AD) is characterized by epidermal barrier dysfunction and immune dysregulation. Notably, metabolic disorders such as obesity can influence AD susceptibility; however, the specific molecular drivers underlying this association, particularly those involving dysregulated RNA metabolism, remain incompletely understood. Our study demonstrates that obesity-associated upregulation of the N⁶-methyladenosine (m⁶A) demethylase FTO in lesional epidermis, specifically in keratinocytes (KCs), drives AD pathology. Integrated transcriptomic and epitranscriptomic sequencing analyses identified Suppressor of Cytokine Signaling 6 (SOCS6) as a key FTO target. Mechanistically, FTO selectively binds and demethylates m⁶A modifications within the coding sequence (CDS) of SOCS6 mRNA, reducing SOCS6 mRNA stability and protein expression. This site-specific epigenetic silencing activates inflammatory programs in KCs. We further identified IL-1β, S100A8, and S100A9 as major downstream effectors of this FTO/SOCS6-m⁶A axis, promoting KCs apoptosis, barrier impairment, and inflammation. Critically, topical FTO knockdown in vivo ameliorated AD-like pathology and restored SOCS6 expression, confirming FTO's causative role. Collectively, we elucidate the FTO/SOCS6-m⁶A epigenetic axis as a fundamental obesity-AD link, highlighting its components as promising therapeutic targets for precision AD management.

Merkel cell carcinoma (MCC) recurs in 40% of patients and 30% will require systemic therapy. While PD-(L)1 immune checkpoint inhibitors (ICIs) have improved outcomes for advanced MCC, over half of patients do not experience long-term disease control. MCC is radiosensitive and there is evidence that radiation therapy (RT) can promote anti-tumor immunity. We performed an analysis of 27 prospectively-followed patients whose MCC progressed on ICI, and who then received RT while continuing ICI. The median progression-free survival (PFS) on ICI alone was 2.8 months. Following disease progression, continuation of ICI, and addition of RT, these same patients had median PFS of 5.1 months (p=0.09). Patients with acquired ICI resistance had lower risk of progression than those with primary resistance (hazard ratio (HR) 0.35, 95% CI: 0.14-0.89, p=0.02). Patients who received a single dose of RT (8 Gray; n=13) had a similar risk of disease progression to those who received multiple fractions (≥20 Gray, n=14; HR 0.87, 95%CI: 0.37-2.00, p = 0.73). RT to all disease sites (n=10) was associated with longer post-RT PFS versus RT to a subset of sites (5.3 vs. 2.8 months). RT was well-tolerated without significant toxicity and is a clinically useful salvage option for ICI-refractory MCC.

A hierarchical organization within tumor underlies the varying capacities of cancer cells to proliferate, metastasize, and drive relapse. Cancer Stem Cells (CSCs) are resistant to conventional therapies, making them critical targets for cancer treatment. Thyroid Hormone (TH), a key regulator of proliferation and differentiation, is tightly controlled by the deiodinase enzymes. By integrating in vivo animal studies in a genetic mouse model of Basal Cell Carcinoma (BCC) with analyses of human BCC specimens, we demonstrate that the Deiodinase Type 3 (D3), the TH-inactivating enzyme, is expressed in the most tumorigenic CSC subpopulation. D3 genetic ablation significantly reduces the CSC population within pro-tumorigenic niches and downregulates key stemness markers, including the transcription factor Sox9. Similarly, systemic induction of hyperthyroidism leads to a reduction of the CSC pool. Importantly, analysis of human BCC specimens revealed that D3 is highly enriched in the CSC niche. Mechanistically, we found that TH treatment suppresses Sox9 expression. These findings demonstrate that D3 sustains the tumorigenic potential of BCC CSCs by protecting them from TH-induced apoptosis and differentiation. Targeting the D3/TH axis may represent a promising therapeutic strategy to reduce the ability to self-renew of CSCs and inhibit tumor progression in BCC.

Photoaging, driven by chronic ultraviolet radiation (UVR), disrupts skin structure and function. Traditional retinoids enhance extracellular matrix (ECM) regeneration but cause irritation. Hydroxypinacolone 9-cis retinoate (9-cis HPR), a derivative of 9-cis retinoic acid, selectively activates RARα and RXRα, improving efficacy and tolerability. In a UVR-induced SKH-1 mouse photoaging model, 9-cis HPR reduced erythema, desquamation, and loss of elasticity while promoting collagen and elastin production. Single-cell RNA sequencing and spatial transcriptomics revealed restoration of fibroblast, basal cell, and melanocyte proportions, suppression of myofibroblast differentiation, and upregulation of ECM-related genes (e.g., Col1a2, Col3a1, Elastin). Additionally, 9-cis HPR inhibited melanogenesis by downregulating melanogenesis-related genes (Tyr, Dct, Tyrp1), melanosome biogenesis genes (Mlana, Pmel), and the melanocyte proliferation gene Kit, likely via ROS suppression. Cell-cell interaction analysis showed that 9-cis HPR promoted fibroblast-driven repair via NPY-NPY1R, PTN-SDC2, and POSTN-ITGA/BV signaling, while inhibiting KITL-KIT-mediated melanocyte proliferation. In a single-blind, split-face clinical trial involving 31 Chinese women, 0.03% 9-cis HPR applied daily for 4 weeks demonstrated comparable or superior improvements in wrinkles, elasticity, hydration, dermal density, and radiance versus 0.3% retinol, without observed irritation. These findings support 9-cis HPR as a safe and effective retinoid that mitigates photoaging through ECM restoration, inflammation modulation, and pigmentation control.

Eradication of Sézary Syndrome (SS) is hampered by genetic and molecular heterogeneity. A better understanding of the putative commonalities underlying SS oncogenicity may help to provide more efficient therapies against this disease. The present work analyzes the whole transcriptome of different patient-derived SS cells (n=7) to identify expression patterns and mutational profiles that may provide clues on new therapeutic options for SS patients. Mononuclear cells were recovered by Ficoll gradient from fresh peripheral blood of SS patients (PBMCs). Selected pathway-based inhibitors were used for in vitro drug testing in SS cells using viability assay and flow cytometry (FC). We validated the usefulness of MALT1 inhibitor MI2 using patient-derived SS cells xenografted into eight NSG mice from patient #26. We identified a high variability in the mutational landscape that converge in a restricted number of altered signaling pathways. In vitro data indicated that cell lines and primary malignant SS cells display different sensitivities against pathway inhibitors. MALT1 inhibition, which impacts on NF-κB signaling, led to a robust effect in vitro that was partially reproduced in the NSG model. Our investigations revealed the actual possibility of inhibiting downstream TCR signaling by CARD11, BCL10 and MALT1 in SS therapy.