Citations

TRAIL is a TNF family ligand that trimerizes TRAIL-R1 (DR4) or TRAIL-R2 (DR5) to induce apoptosis, necroptosis, and/or NF-κB activation in receptor-bearing cells. We previously identified TRAILshort as a splice variant of TRAIL that lacks cysteine 230, cannot trimerize, and acts as a dominant-negative ligand that blocks TRAIL-mediated apoptosis. TRAILshort is expressed on cell surfaces and within extracellular vesicles, enabling it to confer TRAIL resistance to both producing and bystander cells. In this study, we showed that elevated TRAILshort levels were associated with chronic viral infections, cancer, and autoimmune diseases, suggesting a link to impaired immune regulation. Using unbiased phosphoproteomics and mechanistic studies, we demonstrated that TRAILshort binding to DR5 recruited and activated the phosphatase Src homology region 2 domain–containing phosphatase 1 (SHP-1), leading to zeta-chain-associated protein kinase 70 (ZAP-70) dephosphorylation, disruption of ZAP-70–CD3ζ interactions, and impaired T cell receptor signaling, thereby reducing T cell activation, proliferation, and cytokine production in response to antigen or CD3/CD28 ligation. Genetic or pharmacologic SHP-1 inhibition reverses these effects. In humanized mouse models, TRAILshort promoted the persistence of transformed mouse embryonic fibroblasts (MEFs) and L428 and antagonized CD19-directed CAR T cell activity, revealing TRAILshort as an immunomodulator of T cell function with therapeutic implications, including blocking TRAILshort to restore T cell immunity or delivering TRAILshort to enforce tolerance. TRAILshort, a variant of TRAIL, suppresses T cell function and immune responses in cancer and infectious diseases, highlighting its potential as a therapeutic target.

We report an innovative interleaved voltammetric strategy to simultaneously quantify tonic levels of dopamine and serotonin in vivo using a single unmodified microelectrode, advancing our capability to monitor complex neurochemical interactions.

Importance Elevated low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for cardiovascular disease, the leading cause of premature death worldwide. Assessing the LDL-C–related burden is critical for guiding prevention and treatment strategies. Objectives To estimate the global, regional, and national burden of ischemic heart disease and ischemic stroke attributable to elevated LDL-C (relative to 35-54 mg/dL) from 1990 to 2023 and to quantify the contributions of population growth, aging, risk-deleted burden, and exposure changes to burden trends. Design, Setting, and Population This comparative risk assessment, part of the Global Burden of Disease Study 2023, estimated population-level LDL-C exposure and associated health loss in 204 countries and territories. Mean LDL-C levels were estimated using spatiotemporal gaussian process regression based on 806 studies across 161 countries. Relative risks were derived from meta-analyses of 38 randomized clinical trials. Population-attributable fractions for deaths and disability-adjusted life-years (DALYs) were estimated by age and sex for adults aged 25 years or older from 1990 to 2023, with 95% uncertainty intervals. Exposure Population-level LDL-C concentrations. Main Outcomes and Measures Population-attributable fractions, counts, and rates (all ages and age standardized per 100 000) of LDL-C–attributable deaths and DALYs from ischemic heart disease and ischemic stroke, with uncertainty intervals. Results In 2023, elevated LDL-C accounted for 3.6 million deaths (95% uncertainty interval, 2.2-5.4 million; 6.0% of global mortality) and 90.7 million DALYs (95% uncertainty interval, 58.9-123.3 million; 3.2% of DALYs). Although global all-ages rates remained stable, age-standardized death and DALY rates decreased by 45.6% and 39.5%, respectively, since 1990. In 2023, age-standardized LDL-C–attributable DALY rates were highest in Eastern Europe and lowest in high-income Asia-Pacific. One-third of the global LDL-C burden occurred in India and China. Population growth and aging drove the increasing burden, with notable regional disparities in LDL-C exposure and risk-deleted DALY rates shifting toward middle-sociodemographic settings. Conclusions and Relevance Despite declining age-standardized rates, the absolute LDL-C burden has increased since 1990 due to demographic changes and has shifted toward middle-sociodemographic countries. Measurement and surveillance gaps persist. Strengthened prevention, diagnosis, and treatment access strategies are essential to mitigate the health burden of LDL-C.

Abstract Effector gene expression in CD8+ T cells is tightly controlled at the epigenetic and transcriptional levels; however, crucial regulatory signals remain incompletely understood. In this study, we identify dual specificity phosphatase 2 (DUSP2) as a key epigenetic modulator of effector CD8+ T-cell state, by elucidating inhibition of BAF-mediated chromatin opening by DUSP2. Induced downregulation of DUSP2 in human CD8+ T cells enhances cytotoxicity and effector phenotypes by increasing chromatin accessibility through upregulation of BAF subunits, such as SMARCA4, and permitting binding of ETS1 to BAF subunit gene loci and those essential for effector programs. These findings uncover a previously unrecognized role of DUSP2 in the management of the chromatin landscape in effector CD8+ T cells and the epigenetic fine-tuning of their functionality, highlighting DUSP2 as a promising therapeutic target for T cell–based immunotherapy.

Background: Noninvasive tests are well validated in metabolic dysfunction–associated steatotic liver disease, but evidence in metabolic dysfunction and alcohol-associated liver disease (MetALD) and alcohol-associated liver disease (ALD) is limited. We evaluated noninvasive test–based clinical care pathways for fibrosis risk stratification in MetALD and ALD. Methods: This is a multinational, multicenter, cross-sectional study across 35 centers in 16 countries (2013–2025), including adults with MetALD or ALD. Fibrosis was assessed by liver biopsy and/or vibration-controlled transient elastography (VCTE). In biopsy-proven participants, we analyzed the sequential pathway (Fibrosis-4 [FIB-4] first, followed by VCTE for indeterminate FIB-4) to identify advanced fibrosis (≥F3). Diagnostic accuracy was assessed using the AUC. Results: Among 893 participants (41.3% MetALD and 58.7% ALD), the median age was 52 [43.0–61.0] years, and 79.4% were male. The estimated prevalence of advanced fibrosis was 45% (32.2% in MetALD and 54.0% in ALD). Participants with MetALD had a more dysmetabolic profile but lower fibrosis stages than ALD. Among biopsy-proven participants, FIB-4 AUC was 0.720, and VCTE AUC was 0.833. FIB-4 performed better in MetALD than ALD (AUC 0.773 vs. 0.540), while VCTE accuracy was similar across groups. In the sequential pathways, the false-negative rate for advanced fibrosis (misclassified as low risk) was 6.8% (4.9% MetALD and 11.3% ALD). Conclusions: In biopsy-proven patients, FIB-4 performance was acceptable in MetALD but substantially weaker in ALD. The standard 2-step pathway performed adequately in MetALD but missed a clinically meaningful proportion of advanced fibrosis in ALD.

Abstract Introduction Cancer immunotherapy has transformed the treatment landscape by leveraging the immune system to eradicate malignant cells. Among immune effectors, CD8+ T cells play a pivotal role in tumor clearance through recognition and destruction of cancer cells. To effectively counter the rapid proliferation and continuous evolution of cancer, robust effector function of cytotoxic CD8+ T cells is essential. The expression of effector genes in CD8+ T cells is tightly regulated, ensuring that cytotoxic molecules are expressed only at appropriate times and in relevant contexts. We previously reported that upregulation of the gene NKG7 following immunotherapy is critical for clinical response and demonstrated that NKG7 expression is both necessary and sufficient for T cell cytotoxicity. However, the mechanisms governing NKG7 expression in CD8+ T cells remain poorly defined. Methods We performed a cytokine screen to identify potential drivers of NKG7 expression at both the transcriptional and protein levels in cell lines and healthy donor peripheral blood mononuclear cells (PBMC). We employed quantitative RT-PCR, flow cytometry, and Western blotting to determine and validate the expression level of NKG7 and relevant signal molecules. We validated the signal pathways identified in single cell RNAseq data analysis in PD-1 therapy-responsive CD8+ T cells. Results In PBMC derived CD8+ T cells, we found that IL-2 increases NKG7 mRNA levels, correlating with a dose dependent increase in NKG7 protein expression. IL-2—induced NKG7 expression is associated with elevated levels of T-bet, a transcription factor essential for effector T cell differentiation. Consistent with this, scRNA-seq analysis revealed enrichment of the IL-2 signaling pathway in CD8+ T cells responsive to anti—PD-1 therapy. Conclusion Our results suggest that NKG7 is upregulated by IL-2 and T-bet signaling. Due to the critical role of this signaling axis during effector CD8+ T cell differentiation, NKG7 expression may be determined during this phase. Funding Source n/a Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

Abstract Introduction The underlying immunopathogenesis of inflammatory arthritis (IA) immune-related adverse event (irAE) remains obscure. Unlike rheumatoid arthritis (RA), where autoantibodies and B cell dysfunction are central features, the contribution of humoral immunity to IA-irAE is unclear. Methods Here, we performed immunophenotyping of peripheral blood from IA-irAE patients, and compared them with seronegative RA patients, ICI-treated patients without irAE, and healthy controls. Results IA-irAE was marked with increased cytotoxic gene expression and metabolic activation in T cells, and reduced CXCR3 and CCR6 expression in CD4+ T cells. Contrary to seronegative RA, IA-irAE patients displayed no significant elevation in autoantibody levels or atypical CD11c+CD21⁻ B cells. IA-irAE was further characterized by elevated levels of IL-6, IL-12, and type I IFN, which correlated with the T cell activation phenotypes. Conclusion Altogether, our findings define IA-irAE as a disease with certain immunological features distinctive from RA, representing a potentially T cell driven, autoantibody-independent autoimmunity. These results offer insights into immune tolerance breakdown and therapeutic targeting in irAEs. Funding Source National Institute of Arthritis and Musculoskeletal and Skin Diseases Mark E. and Mary A. Davis Initiative in Rheumatoid Arthritis Research Mayo Foundation for Medical Education and Research Topic Categories Basic Autoimmunity (BA)

Abstract Understanding how immune checkpoint inhibitors (ICIs) reshape human T-cell responses requires models that move beyond static transcriptomic snapshots and discrete cell-state classifications. Here, we present an integrative AI-enabled virtual cell framework that represents human CD8⁺ T-cell responses as dynamic and computable systems during ICI therapy. By integrating single-cell RNA sequencing with paired T-cell receptor sequencing within the C2S-scale foundation model, we construct a virtual representation of individual T cells, in which each cell is encoded by a unique functional identity that captures its transcriptional, signaling, and clonal characteristics. Using this framework, we identify a previously unrecognized dynamic latent effector state of CD8⁺ T cells characterized by intermediate expression of effector genes, distinct signaling activity, and ongoing clonal expansion. Across independent patient cohorts, the virtual cell model consistently indicates that ICI therapy mainly acts by unmasking pre-existing effector potential rather than inducing de novo effector differentiation. Notably, this latent effector population remains transcriptionally restrained despite active signaling and clonal expansion, revealing a hidden reservoir of antitumor immune capacity. More broadly, our study demonstrates how AI-enabled virtual cell modeling can reconstruct latent cellular states and their dynamic transitions from multidimensional single-cell data. By incorporating functional identity into virtual cell model, this framework uncovers biologically meaningful yet non-obvious T-cell effector program during cancer immunotherapy and provides a generalizable approach for studying immune dynamics in human disease.

Abstract Background: The limited efficacy of oncolytic virotherapy (OV) in gastrointestinal malignancies has been attributed to an immunologically inert tumor microenvironment. While cisplatin is widely used as a cytotoxic agent, its immunomodulatory effects remain incompletely defined. We hypothesized that cisplatin may reprogram the tumor immune landscape to enable more effective OV-mediated anti-tumor responses. Methods: We evaluated the effects of cisplatin in combination with two distinct oncolytic platforms, vesicular stomatitis virus (VSV) and adenovirus (AdV), across both in vitro and in vivo colorectal cancer models. In vivo efficacy was assessed using MC38 subcutaneous and peritoneal metastatic models, with analysis of tumor growth, survival, and toxicity. Immune profiling was performed using single-cell RNA sequencing (scRNA-seq), flow cytometry, and bulk RNA sequencing to interrogate changes in CD8+ T cell states and functional programs. Guided by these preclinical findings, a clinical trial combining XELOX, PD-1 blockade, and OV therapy was initiated (ChiCTR2500107607). Results: Cisplatin markedly enhanced OV-mediated anti-tumor efficacy across models, resulting in sustained tumor control and improved survival in both subcutaneous and peritoneal disease settings. This effect was conserved across viral platforms, indicating a virus-agnostic interaction. Mechanistically, cisplatin induced a robust interferon (IFN)–dominant transcriptional program, characterized by upregulation of interferon-stimulated genes, including IRF7, IRF9, and ISG15. Single-cell analysis revealed that combination therapy reshaped the CD8+ T cell compartment, promoting the expansion of a population with transcriptional and functional features of central memory T cells (Tcm), alongside reduced exhaustion signatures. These changes were accompanied by enhanced cytokine signaling pathways associated with T cell maintenance and function, including IL-2, IL-7, and IL-15. In vitro, the combination of cisplatin and OV increased tumor cell death and interferon-γ production, supporting a model in which cytotoxic and immunostimulatory effects are mechanistically linked. A phase I clinical trial has been initiated. In gastric cancer, patients with retroperitoneal metastases are being treated with OV in combination with PD-1 blockade (ongoing). In colorectal cancer, the strategy is being evaluated in the neoadjuvant setting with an rectal preservation approach. Conclusions: Our findings identify a previously unrecognized role for cisplatin in priming an interferon-driven immune program that promotes Tcm differentiation and function, thereby enabling durable responses to oncolytic virotherapy. This work provides a mechanistic rationale for leveraging chemotherapy-induced immune reprogramming to enhance viro-immunotherapy and supports the clinical translation of this strategy in gastrointestinal malignancies. Citation Format: Joseph Brandon. Parker, Zhongyi Dong, Tao Liu, Qisen Guo, Haoyu Zhang, Bo Ni, Long Bai, Yiwen Chen, Jiasheng Zong, Xiang Xia, Jiaojiao Zheng, Hoang Tran Pham, Aya Elalfy, Demarcus Ingram, Ahmed Abdel-Hakeem, Muhammad Ali, Shannon Hartzell, Zizhen Zhang, Vivienne Yang. Cisplatin primes an interferon-driven CD8+ central memory T cell program to enable oncolytic virotherapy in gastrointestinal cancer malignancies [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr B024.