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bioRxiv2023

Standardization of suspension and imaging mass cytometry readouts for clinical decision making

Suspension and imaging mass cytometry are single-cell, proteomic-based methods used to characterize tissue composition and structure. Data assessing the consistency of these methods over an extended period of time are still sparse and are needed if mass cytometry-based methods are to be used clinically. Here, we present experimental and computational pipelines developed within the Tumor Profiler clinical study, an observational clinical trial assessing the relevance of cutting-edge technologies in guiding treatment decisions for advanced cancer patients. By using aliquots of frozen antibody panels, batch effects between independent experiments performed within a time frame of one year were minimized. The inclusion of well-characterized reference samples allowed us to assess and correct for batch effects. A systematic evaluation of a test tumor sample analyzed in each run showed that our batch correction approach consistently reduced signal variations. We provide an exemplary analysis of a representative patient sample including an overview of data provided to clinicians and potential treatment suggestions. This study demonstrates that standardized suspension and imaging mass cytometry measurements generate robust data that meet clinical requirements for reproducibility and provide oncologists with valuable insights on the biology of patient tumors.

cancer biology↗

bioRxiv2024

Effector T Cells under Hypoxia have an Altered Transcriptome Similar to Tumor-Stressed T Cells Found in Non-Responsive Melanoma Patients

BackgroundIn the Tumor Microenvironment (TME), hypoxia stands as a significant factor that modulates immune responses, especially those driven by T cells. As T cell-based therapies often fail to work in solid tumors, this study aims to investigate the effects of hypoxia on T cell topo-distribution in the TME, gene expression association with T cell states, and clinical responses in melanoma. MethodsTo generate detailed information on tumor oxygenation and T cell accessibility, we utilized mathematical modeling of human melanoma tissue microarrays (TMAs) that incorporate oxygen supply from vessels, intratumoral diffusion, and cellular uptake. We created tumor maps and derived plots showing the fraction of CD4 and CD8 T cells against the distance to the nearest vessel and oxygen pressure. To assess their function and transcriptional changes caused by hypoxia, effector T cells were generated and cultured under hypoxia (0.5% oxygen) or normoxia (21% oxygen). The T cell hypoxia-transcriptional signature was compared against datasets from msigDB, iATLAS (clinical trials of melanoma patients treated with immune checkpoint inhibitors), ORIEN AVATAR (real-world melanoma patients treated with immune checkpoint inhibitors, ICIs), and a single-cell atlas of tumor-infiltrating lymphocytes (TILs). ResultsWe made three specific observations: 1) in melanoma T cells preferentially accumulated in oxygenated areas close to blood vessels (50-100 micrometers from the vasculature in the regions of high oxygen availability) but not in hypoxic areas far from blood vessels. 2) Our analysis confirmed that under hypoxia, T cell functions were significantly reduced compared to normoxic conditions and accompanied by a unique gene signature. Furthermore, this hypoxic gene signature was prevalent in resting and non-activated T cells. Notably and clinically relevant, the hypoxic T cell gene set was found to correlate with reduced Overall Survival (OS) and reduced progression-free survival (PFS) in melanoma patients, which was more pronounced in non-responder patients undergoing ICI therapy. 3) Finally, compared with a single-cell atlas of tumor-infiltrating T cells, our hypoxia signature aligned with a population of cells at a state termed stress response state (TSTR). ConclusionOur study highlights the critical role of hypoxia in shaping T cell distribution and its correlation with clinical outcomes in melanoma. We revealed a preferential accumulation of T cells in oxygenated areas. Moreover, hypoxic T cells develop a distinct hypoxic gene signature prevalent in resting, non-activated T cells and TSTR that was also associated with poorer outcomes, particularly pronounced among non-responders to ICIs. Key MessagesWhat is already known on this topic: Hypoxia significantly impairs T cell functions, including reduced proliferation and cytokine production. This impairment may contribute to immune evasion and resistance to immune therapies, such as ICIs, adoptive transfer of TILs, and Chimeric Antigen Receptor (CAR) T cells. Despite the established impact of hypoxia on T cell function, the precise spatial distribution of T cells in relation to oxygen availability within the TME and how this affects clinical outcomes in melanoma patients remains unclear. Additionally, the specific transcriptional changes in T cells induced by hypoxia and their prevalence in different T cell states, as well as the implications for resistance to ICIs, have not been thoroughly investigated. Understanding these aspects is crucial for developing targeted therapies to overcome hypoxia-induced resistance and improve immunotherapy efficacy. What this study adds: This study elucidates the profound impact of hypoxia on T cells in melanoma. Our findings reveal that T cells accumulate in well-oxygenated regions near blood vessels, whereas hypoxic conditions significantly impair their proliferation and cytokine production. By addressing the transcriptional changes induced by hypoxia, we demonstrated its prevalence in resting and non-activated T cells and TSTR. Moreover, we found that hypoxia is associated with shorter OS and PFS in melanoma patients, particularly in non-responders to ICIs. This research highlights the critical role of hypoxia in modulating T cell spatial behavior, contributing to immune evasion and poor clinical outcomes in melanoma. How this study might affect research, practice, or policy: The findings emphasizes hypoxias critical role in modulating T cell behavior and its potential as a biomarker for treatment outcomes. These insights could inform the development of therapeutic strategies aimed at improving T cell function in hypoxic TMEs, thereby enhancing the efficacy of immunotherapies for melanoma and other solid tumors. Additionally, the studys results may influence policies regarding the evaluation and implementation of combination therapies that target hypoxia to improve patient outcomes.

immunology↗

bioRxiv2026

FlowTransOP: Distributional Translation of Omics Signatures via Constrained Deep Flow Matching

Observations from pre-clinical models rarely generalize to human patients, leading to many failures in clinical trials. Most existing methods cannot handle domains with non-overlapping features and no paired samples. Here, we developed FlowTransOP to translate biological observations across such domains without requiring 1-to-1 feature mappings and paired data, while providing a guideline for model selection across four translational regimes. We use flow matching to align full domain distributions in a pre-aligned latent space, with a structural regularization term that keeps similar conditions proximate after transformation. FlowTransOP remains competitive with gold-standard approaches requiring paired samples, but outperforms them when pairs become scarce (<35 pairs) or when cross-domain features are only moderately correlated (r<=0.58). Overall, FlowTransOP can translate perturbations between pre-clinical models and patients when direct correspondences are unavailable, enabling reliable therapeutic inference. As a proof-of-concept, we trained a foundational mouse-human transcriptomic map on ARCHS4 and applied it to liver disease predictions.

bioinformatics↗

bioRxiv2025

AURKA inhibition amplifies DNA replication stress to foster WEE1 kinase dependency and synergistic antitumor effects with WEE1 inhibition in cancers

Highly elevated expression of the oncogene Aurora kinase A (AURKA) occurs in numerous human cancers harboring defective p53, nominating AURKA as a potential vulnerability in TP53-mutated cancer. However, clinical trials have indicated modest monotherapy activity of AURKA inhibitors. Here, we demonstrate that AURKA inhibition promotes phosphorylation of Replication Protein A (RPA), resulting in stalled DNA replication fork progression and eliciting a replication stress response in multiple TP53-mutated models, creating a druggable dependence on the mitotic checkpoint kinase WEE1. Combined inhibition of AURKA and WEE1 synergistically enhanced replication stress, tumor-specific apoptotic cell death, and mitotic catastrophe, and lead to marked tumor regression in cell line- and patient-derived xenograft models of TP53-mutated cancer. Our findings define enhanced DNA replication stress as underlying the strong synergy between AURKA and WEE1 inhibitors and offer preclinical confirmation of efficacy, indicating high potential for clinical translation of this synthetic lethal strategy for TP53-mutated carcinomas. Statement of significanceWe demonstrate that a small molecule AURKA inhibitor amplifies DNA replication stress in TP53-mutated carcinomas. This amplification of DNA replication stress can be leveraged this for synthetic lethal therapy in a combination with WEE1 inhibition that enhances antitumor effects in in vitro, in xenografts and in patient-derived xenograft models, advancing a promising novel combination therapy.

cancer biology↗

bioRxiv2025

Monocyte Subset Predict Clinical Outcomes in Fibrotic Hypersensitivity Pneumonitis

RationaleHypersensitivity pneumonitis (HP) is an immunologically mediated form of lung disease resulting from inhalational exposure to various antigens. While there is growing understanding of the immune cells involved in HP, the relationship between clinical outcomes and circulating cell types in HP is not well established. MethodsSingle-cell RNA sequencing was performed on peripheral blood mononuclear cells (PBMCs) from 40 patients with fibrotic hypersensitivity pneumonitis (fHP) in a clinical trial of pirfenidone (NCT02958917). After quality control, we compared data from 33 fHP patients with 36 sex-matched healthy controls (GSE196735). Using Seurat v5, we harmonized the data, formed clusters, and reduced dimensionality through UMAP. Cell type identities were assigned based on a published reference (GSE271789), with clusters annotated for predominant cell type(s) present in at least 30% of the cells. We compared cell type proportions between fHP and HC using the chi-squared test and performed differential expression analysis with DESeq2 on pseudobulk counts, adjusting for sex. Genes significantly upregulated in fHP versus HC at an FDR-adjusted p-value of 0.01 were used to create a multivariate predictive signature for clinical outcomes in fHP participants. Performance was assessed through leave-one-out cross-validation for prediction accuracy. ResultsCompared to HC, fHP has an increased proportion of non-classical CD16+ monocytes (4.2% fHP vs. 1.5% HC), C14+ monocytes with a myeloid-derived dendritic phenotype (2.1% fHP vs. 0.1% HC), platelets (1.0% fHP vs. 0.3% HC), plasmacytoid dendritic cells (0.5% fHP vs. 0.1% HC) and predominantly classical CD14+ monocytes (29.5% fHP vs. 3.4% HC, adjusted-p<0.001). In patients with fHP, cell clusters were associated with the presence of baseline chest CT honeycombing, increased extent of CT lung fibrosis, and worse progression-free survival. CD14+ monocytes consistently demonstrated a high prediction accuracy (>0.90) for these clinical metrics. ConclusionsPeripheral monocyte clusters may be valuable prognostic markers, potentially helping identify at-risk fHP patients.

genetics↗

bioRxiv2018

Profiling gene expression of the host response to a Plasmodium vivax irradiated sporozoite immunization and infectious challenge

The development of vaccines that provide sterile protection against human malaria is a major global public health priority requiring a better understanding of the mechanisms involved in natural and vaccine-induced sterile immunity. RNAseq was used to profile gene expression of peripheral blood samples from 12 Duffy positive (Fy+) (Plasmodium vivax susceptible) volunteers enrolled in a phase 2 trial who were vaccinated with radiation attenuated P. vivax sporozoites (RAS; 5 were protected, 7 not) and from 5 Fy- (P. vivax resistant) volunteers exposed to mosquitoes harboring live non-attenuated sporozoites. Blood samples were obtained before and after immunization as well as after controlled infection with live P vivax sporozoites. The most profound changes in gene expression were observed between baseline and post-challenge, with 97 distinct signatures differentiating protected and not protected Fy+ individuals. Differentiation was also observed between Fy- and Fy+ protected individuals, notably with downregulation of multiple inflammatory responses as well as extracellular matrix-related gene activity. Analysis of transcriptional modules shows that both B-cell and T-cell signaling are reduced while cell cycle regulation, interferon response, and other informative signatures are elevated in individuals who are not protected against malaria. An asymptomatic individual had an intermediate profile indicative of differential transcription associated with pathology and symptomology. Systems biology thus provides insight into how whole malaria-attenuated sporozoites prime the immune system to protect against malaria, as well as the transcription responses that are associated with sterile protection.\n\nAUTHOR SUMMARYTranscriptomic analysis has shed considerable light on the molecular mechanisms of vaccine efficacy against a variety of viral pathogens, but has not yet been used in relation to parasite vaccinology. Here we describe whole peripheral blood gene expression profiling to contrast the contributions of myeloid and lymphoid immune responses to vaccine-induced and natural protection against Plasmodium vivax- mediated malaria. Two modes of modular bioinformatic analyses are applied to RNAseq data from pre- and post-vaccination samples from 19 volunteer participants in a clinical trial investigating the efficacy of an irradiated sporozoite vaccine. During active infection, both B- and T-cell activity are reduced in individuals who are not protected by vaccination relative to those who are protected. Lack of the Fy antigen prevents entry of parasite into red blood cells, thereby providing natural clinical immunity, but we also document differences in T-cell and neutrophil activity in these individuals relative to those protected by irradiation of the parasite. One individual who was asymptomatic for malaria but had blood parasite despite vaccination showed an intermediate response indicating how systems biology approaches can distinguish gene expression associated with pathology and infection.

genomics↗

bioRxiv2025

Structural basis of PPARγ-mediated transcriptional repression by the covalent inverse agonist FX-909

Hyperactivation of peroxisome proliferator-activated receptor gamma (PPAR{gamma})-mediated transcription promotes tumor growth in urothelial (bladder) cancer, which can be inhibited by pharmacological compounds that repress PPAR{gamma} activity. FX-909 is a covalent PPAR{gamma} inverse agonist currently in phase 1 clinical trials for advanced solid malignancies including muscle-invasive bladder cancer. Here, we compared the mechanism of action of FX-909 to other covalent inverse agonists including T0070907, originally reported more than 20 years ago and misclassified as an antagonist, and two recently reported improved covalent inverse agonist analogs, SR33068 and BAY-4931. Functional profiling and NMR studies reveal that FX-909 displays improved corepressor-selective inverse agonism and better stabilizes a transcriptionally repressive PPAR{gamma} LBD conformation compared to T0070907. The crystal structure of PPAR{gamma} LBD cobound to FX-909 and NCoR1 corepressor peptide reveals a repressive conformation shared by other covalent inverse agonists. These findings build on recent studies highlighting the pharmacological significance and clinical relevance of transcriptionally repressive PPAR{gamma} inverse agonists.

biophysics↗

bioRxiv2024

An annotated biobank of triple negative breast cancer patient-derived xenografts featuring treatment-naive and longitudinal samples throughout neoadjuvant chemotherapy

Triple negative breast cancer (TNBC) that fails to respond to neoadjuvant chemotherapy (NACT) can be lethal. Developing effective strategies to eradicate chemoresistant disease requires experimental models that recapitulate the heterogeneity characteristic of TNBC. To that end, we established a biobank of 92 orthotopic patient-derived xenograft (PDX) models of TNBC from the tumors of 75 patients enrolled in the ARTEMIS clinical trial (NCT02276443) at MD Anderson Cancer Center, including 12 longitudinal sets generated from serial patient biopsies collected throughout NACT and from metastatic disease. Models were established from both chemosensitive and chemoresistant tumors, and nearly 30% of PDX models were capable of lung metastasis. Comprehensive molecular profiling demonstrated conservation of genomes and transcriptomes between patient and corresponding PDX tumors, with representation of all major transcriptional subtypes. Transcriptional changes observed in the longitudinal PDX models highlight dysregulation in pathways associated with DNA integrity, extracellular matrix interactions, the ubiquitin-proteasome system, epigenetics, and inflammatory signaling. These alterations reveal a complex network of adaptations associated with chemoresistance. This PDX biobank provides a valuable resource for tackling the most pressing issues facing the clinical management of TNBC, namely chemoresistance and metastasis.

cancer biology↗

bioRxiv2016

Partial derivatives meta-analysis: pooled analyses when individual participant data cannot be shared

Joint analysis of data from multiple studies in collaborative efforts strengthens scientific evidence, with the gold standard approach being the pooling of individual participant data (IPD). However, sharing IPD often has legal, ethical, and logistic constraints for sensitive or high-dimensional data, such as in clinical trials, observational studies, and large-scale omics studies. Therefore, meta-analysis of study-level effect estimates is routinely done, but this compromises on statistical power, accuracy, and flexibility. Here we propose a novel meta-analytical approach, named partial derivatives meta-analysis, that is mathematically equivalent to using IPD, yet only requires the sharing of aggregate data. It not only yields identical results as pooled IPD analyses, but also allows post-hoc adjustments for covariates and stratification without the need for site-specific re-analysis. Thus, in case that IPD cannot be shared, partial derivatives meta-analysis still produces gold standard results, which can be used to better inform guidelines and policies on clinical practice.

Bioinformatics↗

bioRxiv2019

Aberrant Clonal Hematopoiesis Following Lentiviral Transduction of HSPC in a Rhesus Macaque

Lentiviral vectors (LV) have been used for the delivery of genes into hematopoietic stem and progenitor cells (HSPC) in clinical trials worldwide. LV, in contrast to retroviral vectors, have not been associated with insertion site-associated malignant clonal expansions, and thus have been considered safer. Here, however, we present a case of markedly abnormal dysplastic clonal hematopoiesis impacting the erythroid, myeloid and megakaryocytic lineages in a rhesus macaque transplanted with HSPCs that were transduced with a LV containing a strong retroviral murine stem cell virus (MSCV) constitutive promoter-enhancer in the LTR. 9 insertions were mapped in the abnormal clone, resulting in overexpression and aberrant splicing of several genes of interest, including the cytokine stem cell factor and the transcription factor PLAG1. This case represents the first clear link between a lentiviral insertion-induced clonal expansion and a clinically abnormal transformed phenotype following transduction of normal primate or human HSPC, and are thus concerning, and suggest that strong constitutive promoters should not be included within LV vectors.

molecular biology↗

bioRxiv2026

Multiomic dissection of HR+/HER2- invasive lobular breast carcinoma reveals mobilized yet dysfunctional anti-tumor immunity shaped by tumor-stroma crosstalk and impaired antigen presentation

ContextImmunotherapy based on immune checkpoint inhibitors (ICI) revolutionized the treatment of triple-negative (TN) breast carcinomas (BC), but remains more challenging in HR+/HER2- BCs. Because invasive lobular carcinomas (ILC) generally exhibit low immune infiltration, ICIs were largely overlooked in this pathological type. The only clinical trial of ICIs dedicated to ILCs showed disappointing results, notably in HR+/HER2- cases. The immune landscape of HR+/HER2- ILCs has been poorly described. High level of tumor-infiltrating lymphocytes (TIL) was associated with worse prognosis in HR+/HER2- ILCs. A better characterization of the immune landscape of HR+/HER2- ILCs could clarify the poor efficiency of ICIs and the negative prognostic value of TILs, and reveal complementary targets able to increase immunotherapy efficiency. MethodWe comprehensively characterized the immune landscape of HR+/HER2- ILCs, comparatively to HR+/HER2- invasive ductal carcinomas (IDC), by applying multi-omics and multi-scale analysis (gene expression at the bulk and single-cell levels, and protein-based spatial analysis) to clinical samples. ResultsWhile the overall level of immune infiltration was comparable between both pathological types, the quality of immune infiltrate differed markedly. Comparatively to HR+/HER2- IDCs, HR+/HER2- ILCs were enriched in immune cells and tertiary lymphoid structures with anti-tumor potential, presented more spatial proximity between cancer cells and CD8+ cytotoxic T cells, and stronger theorical vulnerability to ICIs. However, in HR+/HER2- ILCs, anti-tumor response was defective; CD8+ cytotoxic T cells failed to fully unleash their cytotoxic function and CD4+ helper T cells evidenced a pro-tumoral and naive phenotype. Furthermore, antigen-presenting compartment was defective, altogether embedded in a stronger immunosuppressive environment, enriched in immunoregulatory cancer-associated fibroblasts (iCAF). ConclusionThis study contributes to explain the lesser efficiency of PD-1/PD-L1-based ICIs in HR+/HER2-ILCs by comparison with HR+/HER2- IDCs, by shedding light on a complex ecosystem where tumor cells shape a distinctive stroma that contribute to prevent anti-tumor immune response activation. Altogether, our findings further support the rationale for combining iCAF-targeting strategy with an ad hoc immunotherapy (such as an anti-VTCN1/B7-H4 antibody-drug conjugates for example). Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=150 SRC="FIGDIR/small/728418v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1dfbc7eorg.highwire.dtl.DTLVardef@1d030a7org.highwire.dtl.DTLVardef@12a3e84org.highwire.dtl.DTLVardef@6e6139_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_ST_ABSWHAT IS ALREADY KNOWN ON THIS TOPICC_ST_ABSO_LIImmune cells infiltrate both HR+/HER2- IDC and HR+/HER2- ILC tumors, but current ICIs are less effective in HR+/HER2- ILCs than HR+/HER2- IDCs. C_LI WHAT THIS STUDY ADDSO_LIThe anti-tumor immune response is mobilized but not effective in HR+/HER2- ILCs. C_LIO_LIA complex ecosystem - composed of immunoregulatory cancer-associated fibroblasts, high levels of TGFa, prostaglandin, acidosis, and a lack of antigen-presenting cells - prevents anti-tumor CD8+ cytotoxic T cell activation in HR+/HER2- ILCs. C_LI HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE, OR POLICYO_LITargeting the PD-1/PD-L1 axis is not the appropriate therapeutic strategy for HR+/HER2- ILCs. A more complex approach should be considered, notably those combining other immune-based strategies and iCAF targeting, which may offer a better chance to eradicate HR+/HER2- ILC tumor cells. C_LI

cancer biology↗

bioRxiv2022

Type I PRMT inhibitor MS023 promotes SMN2 exon 7 inclusion and synergizes with nusinersen to rescue the phenotype of SMA mice

Spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality. The advent of approved treatments for this devastating condition has significantly changed SMA patients life expectancy and quality of life. Nevertheless, these are not without limitations, and research efforts are underway to develop new approaches to be used alone and in combination, to ensure improved and long-lasting benefits for SMA patients. Protein arginine methyltransferases (PRMT) are emerging as druggable epigenetic targets, with several small molecule PRMT inhibitors already in clinical trial stage. From a screen of highly potent and selective next generation epigenetic small molecules, we have identified MS023, a potent and selective type I PRMT inhibitor, able to promote SMN2 exon 7 inclusion and increase SMN protein levels in preclinical SMA model, by inhibiting the binding of splicing factor hnRNPA1 to SMN2 pre-mRNA. Treatment of SMA mice with MS023 results in amelioration of the disease phenotype, with strong synergistic amplification of the positive effect when delivered in combination with the SMN2-targeting antisense oligonucleotide nusinersen. Moreover, transcriptomic analysis revealed that MS023 treatment has very minimal off-target effects and that the added benefit of the combination therapy is mainly attributable to targeting neuroinflammation. Our study warrants further clinical investigation of PRMT inhibition both as a stand-alone and add-on therapy for SMA patients.

neuroscience↗

bioRxiv2023

TNF-NFkB-p53 axis restricts in vivo survival of hPSC-derived dopamine neuron

Ongoing, first-in-human clinical trials illustrate the feasibility and translational potential of human pluripotent stem cell (hPSC)-based cell therapies in Parkinsons disease (PD). However, a major unresolved challenge in the field is the extensive cell death following transplantation with <10% of grafted dopamine neurons surviving. Here, we performed a pooled CRISPR/Cas9 screen to enhance survival of postmitotic dopamine neurons in vivo. We identified p53-mediated apoptotic cell death as major contributor to dopamine neuron loss and uncovered a causal link of TNFa-NF{kappa}B signaling in limiting cell survival. As a translationally applicable strategy to purify postmitotic dopamine neurons, we performed a cell surface marker screen that enabled purification without the need for genetic reporters. Combining cell sorting with adalimumab pretreatment, a clinically approved and widely used TNFa inhibitor, enabled efficient engraftment of postmitotic dopamine neurons leading to extensive re-innervation and functional recovery in a preclinical PD mouse model. Thus, transient TNFa inhibition presents a clinically relevant strategy to enhance survival and enable engraftment of postmitotic human PSC-derived dopamine neurons in PD. HighlightsO_LIIn vivo CRISPR-Cas9 screen identifies p53 limiting survival of grafted human dopamine neurons. C_LIO_LITNF-NF{kappa}B pathway mediates p53-dependent human dopamine neuron death C_LIO_LICell surface marker screen to enrich human dopamine neurons for translational use. C_LIO_LIFDA approved TNF-alpha inhibitor rescues in vivo dopamine neuron survival with in vivo function. C_LI

neuroscience↗

bioRxiv2024

AhR-Ovol1-Id1 regulatory axis in keratinocytes promotes skin homeostasis against atopic dermatitis

Skin is our outer permeability and immune defense barrier against myriad external assaults. Aryl hydrocarbon receptor (AhR) senses environmental factors and regulates barrier robustness and immune homeostasis. AhR agonist is in clinical trial for atopic dermatitis (AD) treatment, but the underlying mechanism of action remains ill-defined. Here we report OVOL1/Ovol1 as a conserved and direct transcriptional target of AhR in epidermal keratinocytes. We show that OVOL1/Ovol1 impacts AhR regulation of keratinocyte gene expression, and Ovol1 deletion in keratinocytes hampers AhRs barrier promotion function and worsens AD-like inflammation. Mechanistically, we identify Ovol1s direct downstream targets genome-wide, and provide in vivo evidence for Id1s critical role in barrier maintenance and disease suppression. Furthermore, our findings reveal an IL-1/dermal {gamma}{delta}T cell axis exacerbating both type 2 and type 3 immune responses downstream of barrier perturbation in Ovol1-deficient AD skin. Finally, we present data suggesting the clinical relevance of OVOL1 and ID1 function in human AD. Our study highlights a keratinocyte-intrinsic AhR-Ovol1-Id1 regulatory axis that promotes both epidermal and immune homeostasis against AD-like inflammation, implicating new therapeutic targets for AD.

molecular biology↗

bioRxiv2025

EVA: a Foundation Model Advancing Translational Drug Development in Immuno-Inflammation

Drug development is a lengthy and high-risk process, with most investigational drug candidates failing in phase II randomized clinical trials (RCT) due to insufficient efficacy. It makes early prediction of trial outcomes crucial for reducing attrition and guiding strategic decisions, especially in immunology and inflammation (I&I) diseases. Herein, we present EVA, the first pre-trained foundation model in complex inflammatory diseases tailored to support drug development. EVA learns generalizable patterns from large-scale data of cell biology and immunology, enabling superior predictive performance and generalization compared to traditional approaches. EVA is pre-trained on tens of millions of single-cell RNA-seq samples and tens of thousands of bulk RNA-seq samples from I&I diseases patients, enabling it to learn disease-relevant transcriptomic patterns in this therapeutic area. By fine-tuning EVA in few-shot settings on both preclinical (mouse) and clinical (human) data and harnessing its wide pre-training knowledge, EVA predicts drug responses in I&I with high precision at both cohort and patient levels, as illustrated by accurate forecasting of anti-TNF therapeutic activity in ulcerative colitis. By deciphering its decision process, we further highlight that EVAs ability to stratify patients based on predicted drug response can also be leveraged to discover drug response biomarkers as early as preclinical stages. EVAs applications in precision immunology encompass therapeutic target validation prior to clinical entry, identification of patient subpopulations most likely to benefit from treatment, and comparative efficacy analysis against competitor compounds. EVAs versatility makes it an invaluable tool for strategic decision-making throughout the drug development pipeline: by leveraging it to prioritize the most promising drug candidates and optimize RCT designs, it can contribute to reduce late-stage failures and accelerate the delivery of effective therapies. Overall, this work represents a significant advancement in utilizing a pre-trained foundation model for precision drug development in complex inflammatory diseases. Graphical abstractEVA is a pre-trained foundation model specific to immune-mediated inflammatory diseases. It enables the prediction of therapeutic efficacy in patients leveraging data from preclinical disease models. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=73 SRC="FIGDIR/small/651839v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@1c783f1org.highwire.dtl.DTLVardef@1a760d9org.highwire.dtl.DTLVardef@1c7748aorg.highwire.dtl.DTLVardef@1b44f82_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2025

Periodic and aperiodic contributions to EEG delta power are translatable and complementary Angelman syndrome biomarkers

Angelman syndrome (AS) is a neurodevelopmental disorder caused by loss of maternal UBE3A expression. With promising AS therapies now in clinical trials, there is a pressing need for reliable and translatable biomarkers. Elevated EEG delta power is a hallmark of AS and a promising biomarker, but traditional measures conflate delta oscillations with broadband spectral shifts, limiting interpretability and utility. We dissociated periodic and aperiodic contributions to delta power using spectral parameterization in children with AS and Ube3a mutant mice. In both species, elevated delta power reflected a combination of increased periodic delta oscillations and elevated aperiodic slope and offset. These features were linked to different behavioral domains and followed divergent developmental trajectories, suggesting distinct underlying mechanisms. Together, our findings establish aperiodic changes as a novel translatable EEG biomarker for AS and support the complementary use of periodic and aperiodic features in preclinical and clinical research.

neuroscience↗

bioRxiv2022

Aotus nancymaae model predicts human immune response to the placental malaria vaccine candidate VAR2CSA

Placental malaria vaccines (PMV) are being developed to prevent severe sequelae of placental malaria (PM) in pregnant women and their offspring. The leading candidate vaccine antigen VAR2CSA mediates parasite binding to placental receptor chondroitin sulfate A (CSA). Despite promising results in small animal studies, recent human trials of the first two PMV candidates (PAMVAC and PRIMVAC) generated limited cross-reactivity and cross-inhibitory activity to heterologous parasites. Here, we immunized Aotus nancymaae monkeys with three PMV candidates (PAMVAC, PRIMVAC and ID1-ID2a_M1010) adjuvanted with Alhydrogel(R), and exploited the model to investigate boosting of functional vaccine responses during PM episodes as well as with nanoparticle antigens. PMV candidates induced high levels of antigen-specific IgG with significant cross-reactivity across PMV antigens by ELISA. Conversely, PMV antibodies recognized native VAR2CSA and blocked CSA-adhesion of only homologous parasites and not heterologous parasites. PM episodes did not significantly boost VAR2CSA antibody levels or serum functional activity; nanoparticle and monomer antigens alike boosted serum reactivity but not functional activities. Overall, PMV candidates induced functional antibodies with limited heterologous activity in Aotus monkeys, similar to responses reported in humans. The Aotus model appears suitable for preclinical down-selection of PMV candidates and assessment of antibody boosting by PM episodes. Research in Context Evidence before this studyThe Plasmodium falciparum erythrocyte membrane protein VAR2CSA is the leading vaccine candidate antigen to protect pregnant women against placental malaria (PM), which causes serious adverse pregnancy outcomes particularly in first-time mothers living in malaria-endemic areas. Two VAR2CSA-based vaccines (PAMVAC and PRIMVAC) induced strong heterologous functional antibodies in small animals, but induced antibodies with limited cross-inhibitory functional activity in human clinical trials. These observations highlighted the need to establish new animal models that could better recapitulate human pathogenesis and immunity. In ongoing development of a nonhuman primate model for PM, we established an Aotus nancymaae model susceptible to P. falciparum infection during pregnancy that reproduces all the immunoparasitological and histological features of human PM. In this study, we explore the new Aotus model as a platform for evaluating PM vaccine (PMV) immunogenicity and for boosting of vaccine responses during PM episodes. Added value of this studyIn this manuscript, we demonstrate that PMV (including PAMVAC and PRIMVAC) are immunogenic in Aotus monkeys, inducing antibodies with mainly homologous and little heterologous functional activity, as seen in humans but contrary to preclinical reports on these vaccines in small animals. Implications of all the available evidenceOur findings suggest Aotus is a suitable model to assess immunogenicity of VAR2CSA-derived vaccines, in contrast to small animal models. PMV data from human trials and Aotus monkeys suggest that improvements to current VAR2CSA immunogens and/or adjuvants are needed to enhance protective antibody responses, as are studies that evaluate the potential for natural infection to boost vaccine antibody in pregnancy. Therefore, the Aotus PM model may be useful to assess second-generation PMVs seeking to increase strain-transcending activity and to prioritize these for further clinical development.

immunology↗

bioRxiv2024

Single Cell Analysis of Treatment-Resistant Prostate Cancer: Implications of Cell State Changes for Cell Surface Antigen Targeted Therapies

Targeting cell surface molecules using radioligand and antibody-based therapies has yielded considerable success across cancers. However, it remains unclear how the expression of putative lineage markers, particularly cell surface molecules, varies in the process of lineage plasticity, wherein tumor cells alter their identity and acquire new oncogenic properties. A notable example of lineage plasticity is the transformation of prostate adenocarcinoma (PRAD) to neuroendocrine prostate cancer (NEPC)--a growing resistance mechanism that results in the loss of responsiveness to androgen blockade and portends dismal patient survival. To understand how lineage markers vary across the evolution of lineage plasticity in prostate cancer, we applied single cell analyses to 21 human prostate tumor biopsies and two genetically engineered mouse models, together with tissue microarray analysis (TMA) on 131 tumor samples. Not only did we observe a higher degree of phenotypic heterogeneity in castrate-resistant PRAD and NEPC than previously anticipated, but also found that the expression of molecules targeted therapeutically, namely PSMA, STEAP1, STEAP2, TROP2, CEACAM5, and DLL3, varied within a subset of gene-regulatory networks (GRNs). We also noted that NEPC and small cell lung cancer (SCLC) subtypes shared a set of GRNs, indicative of conserved biologic pathways that may be exploited therapeutically across tumor types. While this extreme level of transcriptional heterogeneity, particularly in cell surface marker expression, may mitigate the durability of clinical responses to novel antigen-directed therapies, its delineation may yield signatures for patient selection in clinical trials, potentially across distinct cancer types. SIGNIFICANCE STATEMENTTreatment of prostate cancer is rapidly evolving with several promising new drugs targeting different cell surface antigens. Selection of patients most likely to benefit from these therapies requires an understanding of how expression of these cell surface antigens varies across patients and how they change during disease progression, particularly in tumors that undergo lineage plasticity. Using immunohistochemistry and single cell mRNA sequencing, we reveal heterogeneity of cell states across a cohort of advanced disease prostate cancer patients; this heterogeneity is not captured by conventional histology-based designations of adenocarcinoma and neuroendocrine prostate cancer. We show these cell states can be identified by gene regulatory networks that could provide additional diagnostic precision based on their correlation with clinically relevant cell surface antigen expression.

cancer biology↗