Hong Liu

Physical activity has been linked to immunee regulation in several autoimmune diseases, but its association with autoimmune bullous skin diseases (AIBD), mainly pemphigus and pemphigoid, has not been adequately evaluated. We examined the association between regular physical activity and incident AIBD in 476,057 UK Biobank participants. Multivariable-adjusted Cox models were used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) for AIBD risk according to habitual physical activity. We also assessed joint associations with polygenic risk and performed mediation analysis. During a median follow-up of 15.21 years, 272 incident AIBD cases were documented, including 61 pemphigus and 211 pemphigoid cases. Physically active participants had a 31% lower risk of AIBD than inactive participants (adjusted HR 0.69, 95% CI 0.54–0.88). Similar associations were observed for pemphigus (HR 0.53) and pemphigoid (HR 0.72). Individuals with high genetic risk who were physically inactive had a higher risk than physically active individuals with low genetic risk (HR 2.12, 95% CI 1.47–3.07). In an exploratory mediation analysis, BMI accounted for 8.86 % of the association. These findings suggest that regular physical activity is associated with a lower risk of AIBD after adjustment for genetic susceptibility and other risk factors.

Circadian clock perturbation frequently occurs in cancer and facilitates tumor progression by regulating malignant growth and shaping the immune microenvironment. Emerging evidence has indicated that clock genes are disrupted in melanoma and linked to immune escape. Herein, we found that the expression of retinoic acid receptor–related orphan receptor-α (RORA) is downregulated in melanoma patients and that patients with higher RORA expression have a better prognosis after immunotherapy. Additionally, RORA was significantly positively correlated with T-cell infiltration and recruitment. Overexpression or activation of RORA stimulated cytotoxic T-cell–mediated antitumor responses. RORA bound to the CD274 promoter and formed an inhibitory complex with HDAC3 to suppress PD-L1 expression. In contrast, the DEAD-box helicase family member DDX3X competed with HDAC3 for binding to RORA, and DDX3X overexpression promoted RORA release from the suppressive complex and thereby increased PD-L1 expression to generate an inhibitory immune environment. The combination of a RORA agonist with an anti-CTLA4 antibody synergistically increased T-cell antitumor immunity in vivo. A score based on the combined expression of HDAC3, DDX3X, and RORA correlated with immunotherapy response in melanoma patients. Together, this study elucidates a mechanism of clock component–regulated antitumor immunity, which will help inform the use of immunotherapy and lead to improved outcomes for melanoma patients receiving combined therapeutic treatments.Significance:RORA forms a corepressor complex to inhibit PD-L1 expression and activate antitumor T-cell responses, indicating that RORA is a potential target and predictive biomarker to improve immunotherapy response in melanoma patients.

Melanoma, a malignant tumor originating from melanocytes, accounts for only 4% of all skin cancers but is responsible for 75% of skin cancer-related deaths. In recent years, its incidence has steadily increased. Targeted therapies and immunotherapies have made significant strides, emerging as the most effective treatments for metastatic melanoma. Immune checkpoint blockades (ICBs) have become a central component of systemic therapy for advanced melanoma. However, their clinical use is limited by immune-related toxicities, primary and acquired resistance, and marked inter-patient heterogeneity in response. As a result, personalized treatment approaches are urgently needed. This paper provides a comprehensive review of recent advancements in melanoma immunotherapy, synthesizing findings from existing research and clinical trials. It highlights the progress made in understanding various immune checkpoints in melanoma and the outcomes of clinical trials involving different ICBs. The aim is to inform clinicians and patients about the latest developments in ICBs therapy while underscoring the critical role of personalized medicine in addressing the diverse needs of patients. Ultimately, the research seeks to catalyze further exploration and innovation in melanoma treatment.

Metabolic dysregulation within the epithelial immune microenvironment (EIME) drives chronic inflammatory skin diseases like psoriasis, but the immune mechanisms and downstream consequences remain unclear. Here we perform in-depth metabolomic analysis showing that nucleotide metabolism is enhanced in psoriatic patients, with elevated adenosine levels closely correlating with disease severity. Single-cell and spatial transcriptomics analyses revealed that adenosine is primarily generated from a population of CD73^high fibroblasts in psoriatic skin through enhanced metabolic processes and catalytic capability. Adenosine acts as a mediator between fibroblasts and keratinocytes, causing mitochondrial dysfunction and generating oxidative stress, resulting in the release of pro-inflammatory mediators in keratinocytes via ADORA2B. Deletion of Cd73 in fibroblasts, Adora2b in keratinocytes, or the use of pharmacological inhibitors of the pathways involved, reduces epidermal inflammation in the imiquimod- and IL-23A-induced mouse skin inflammation models. Our study thus identifies the CD73^high fibroblast subsets as regulators of epithelial inflammation through metabolic microenvironment interactions with keratinocytes, providing proof of principle for therapeutic strategies targeting fibroblast-keratinocyte crosstalk in inflammatory skin diseases.

Dysregulation of thymic T cell development compromises immune homeostasis and can lead to leukemic transformation, but the molecular mechanisms linking developmental signals, proliferative cues, and leukemogenesis remain incompletely understood. Here, we integrate deubiquitinase library screening and publicly available single-cell RNA sequencing to analyze mouse and human thymocytes. We find the deubiquitinase USP10 to be expressed in thymocytes, and also elevated in peripheral blood from patients with T-cell acute lymphoblastic leukemia (T-ALL) compared to healthy controls; by contrast, T cell-specific USP10 deficiency blocks mouse thymocyte proliferation and differentiation. Mechanistically, USP10 interacts with SOX4, de-ubiquitinating and protecting SOX4 from degradation to promote thymocyte proliferation, with SOX4 overexpression restoring thymocyte differentiation in USP10-deficient mice. Lastly, MYC induces Usp10 expression, and pharmacologic inhibition of USP10 delays MYC-driven leukemogenesis in a mouse leukemia model. Our results thus identify USP10 as coordinator of developmental signals and oncogenic processes in thymocytes, and implicate USP10 as a potential target for T-ALL therapy.