Biology subjects

Lee, E.

Publications and source records attributed to Lee, E..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Cue-Dependent Fear Learning Drives Nucleus Accumbens Spine Plasticity

Nucleus accumbens (NAc) dopamine 2 receptor expressing medium spiny neurons (D2-MSNs) are involved in stress and aversive learning, where repeated stress increases excitatory spine density. Whether this plasticity reflects cue-specific learning or generalized stress response remains unknown. Using Pavlovian fear conditioning in Tac1-Cre/Tdtomato mice, we dissociated associative plasticity from the effects of foot shock stress. Acute fear conditioning produced distinct physiological outcomes between stress in the presence or absence of a cue. Conditioning for 7 days consolidated cue learning and increased excitatory transmission frequency via an increase in the total spine density. However, repeated exposure to foot shock did not lead to this synaptic remodeling. Our results suggest that morphological changes supporting synaptic plasticity on NAc D2-MSNs are due to cue-dependent learning, but not foot shock stress alone. We propose that NAc D2-MSNs encode learning and response to threat cues, which may heighten later stress responsivity.

neuroscience↗

bioRxiv2026

Between- and Within-subject Variability in Actigraphy Data: A Case Study on Sleep Patterns in Schizophrenia

Variability in longitudinal health outcomes provides critical insight into disease dynamics, yet most statistical analyses continue to prioritize mean trajectories. This limitation is particularly consequential in psychiatric and mobile health (mHealth) research, where intensive repeated measurements increasingly reveal pronounced heterogeneity and temporal instability that cannot be captured by average responses alone. Standard mixed-effects models typically impose homoscedastic variance assumptions and relegate variability to a nuisance component, despite mounting evidence that both variability information, at both between- and within-subject level, carry independent clinical significance. Here, we describe an improved mixed-effects location-scale model for longitudinal outcomes that simultaneously characterizes mean structure, between-subject heterogeneity, and within-subject fluctuations. The proposed framework explicitly links variance components to both time-invariant and time-varying covariates, extending classical mixed-effects models to accommodate heteroscedastic and dynamically evolving variability. By jointly modeling location and scale parameters, the method enables direct inference on variability (or stability) of the data alongside mean trends. We evaluated the approach using an actigraphy-based mHealth case study of sleep patterns in schizophrenia. Our results demonstrate that explicitly modeling variability uncovers clinically relevant structure obscured by mean-based analyses, underscoring the importance of variability-aware modeling for modern longitudinal and mHealth research.

neuroscience↗

bioRxiv2026

Deep Plasma Proteomics Coupled with Functional Genomics Reveals Drivers of Parkinson's Disease Progression and Levodopa Response

Parkinsons disease (PD) is a progressive neurodegenerative disorder lacking disease-modifying therapies, and its clinical management is limited by the absence of accessible biomarkers for tracking disease progression and treatment response. To map these complex disease trajectories, we implemented an ultra-deep plasma proteomics workflow integrating Mag-Net extracellular vesicle enrichment with Orbitrap Astral mass spectrometry to profile longitudinal samples from PD patients. This approach quantified 6,481 plasma proteins at unprecedented depth in PD studies, revealing distinct signatures directly associated with disease duration and dopaminergic therapy exposure. Candidate biomarkers were subsequently validated in an independent cohort using ELISA, demonstrating robust predictive utility in AI-driven prediction models. To uncover the mechanistic drivers underlying these systemic changes, we intersected our proteomic data with novel proteome-wide gene overexpression perturbation screens designed to identify regulators of alpha-synuclein pre-formed fibril (PFF) uptake and PFF-induced neuronal toxicity. Finally, an integrative network analysis combining three independent proteome-wide assays revealed that key pathological hubs, such as CD14, IFNG, and PLAT, are targets of currently approved pharmacological agents. Collectively, these findings provide a comprehensive, systems-level map for PD biomarker discovery and highlight druggable pathways to advance precision medicine strategies.

neuroscience↗

bioRxiv2026

Context-aware Multi-Property Antibody Predictor: a Novel Framework Integrating Text and Protein Language Models

Recent advances in Machine Learning have transformed antibody development through in-silico models, accelerating therapeutic candidate identification. However, challenges persist: rapid adaptation of property predictors to laboratory-specific assays with incomplete datasets; batch effects introducing systematic bias; assay costs necessitating efficient unseen property prediction. We introduce a novel multi-modal architecture featuring specialized tokenization and embedding projection that integrates text and protein language models (pLM) and a learning strategy to enable in-context learning for multi-property prediction without learning shortcuts. Our framework enables prompting without dictionary merging across modalities, creating a compact model capable of in-context learning for multi-property prediction. The orchestrating model avoids pLM-to-text projection while enabling inference-time adaptation without retraining. Using 876,898 antibodies with batch effect simulation, our architecture achieved Spearmans {rho}>0.8 across multiple developability properties, significantly outperforming fine-tuned multimodal-LLMs and showed the ability of leveraging correlation between properties for prediction. This approach has the potential to address critical antibody development challenges.

bioinformatics↗

bioRxiv2025

HIV Nef amplifies mechanical heterogeneity to promote immune evasion

Intracellular pathogens must evade cytotoxic immunity to establish persistent infection. Although immune escape is typically viewed through a biochemical lens, the ability of certain pathogens to alter the mechanical properties of infected cells suggests that biophysical mechanisms may also contribute to the process. Here, we show that a subset of CD4+ T cells infected with the human immunodeficiency virus (HIV) resist elimination through a soft phenotype that inhibits killing by mechanosensitive cytotoxic T lymphocytes (CTLs). This phenotype arises from the combined effects of the HIV virulence factor Nef, which remodels the actin cytoskeleton, and intrinsic heterogeneity in the basal cytoskeletal properties of infected T cells. Pharmacological or genetic perturbations that reverse Nef signaling to the cytoskeleton or that stiffen the filamentous-actin cortex sensitize infected cells to CTL-mediated lysis. Taken together, these findings define a novel, biophysical paradigm of immune evasion with implications for HIV cure strategies.

immunology↗

bioRxiv2025

The Role of Pavlovian Bias in Smoking Cessation Success and Neurocognitive Alterations During Nicotine Withdrawal

BackgroundInability to manage conflicts between multiple decision-making systems is associated with various mental disorders including addiction. The imbalance between the Pavlovian and instrumental systems may contribute to smoking cessation failure and relapse, as excessive Pavlovian motivation may override goal-directed quitting attempts. However, the exact role of the Pavlovian bias in smoking cessation and its neurocognitive mechanisms remain poorly understood. MethodsEighty-six smokers participated in a smoking cessation clinic, completing the well-established orthogonalized go-nogo task before and after the intervention. We applied computational modeling and functional magnetic resonance imaging (fMRI) analyses to investigate the role of Pavlovian bias and its neural correlates in predicting smoking cessation outcomes. ResultsComputational modeling revealed that higher levels of Pavlovian bias were associated with treatment failures. Importantly, Pavlovian bias significantly moderated the relationship between clinic participation rate and the likelihood of smoking cessation, suggesting that such bias can undermine motivational effort to quit. Furthermore, individuals who successfully quit smoking exhibited increased Pavlovian bias toward reward following cessation, indicating a potential cognitive mechanism underlying the relapse cycle. Complementary fMRI analyses demonstrated that Pavlovian bias influenced valence encoding in the ventromedial prefrontal cortex (vmPFC), suggesting altered decision-making neural circuits. ConclusionsPavlovian bias can be a critical risk factor of relapse in the smoking population, while this bias can be increased in response to nicotine abstinence. Moreover, the results highlight the roles of the vmPFC in decision-making under Pavlovian-instrumental conflict, providing insights into the neural underpinnings of relapse vulnerability. Understanding these mechanisms may guide targeted interventions to enhance smoking cessation outcomes.

neuroscience↗

bioRxiv2025

Somatic copy number mutations contribute to fitness in transplantation models of spontaneous human breast cancer metastasis

The contribution of somatic gene dosage mutations (CNA) to breast cancer metastasis remains poorly defined. Using 9 transplantable human neoadjuvant-naive triple-negative breast cancer xenografts, we studied the fitness of copy number clones in spontaneous metastasis from orthotopic transplant sites. Metastatic site preference was strongly patient-dependent, and the emergence of metastases exhibited a general trend toward slower growth at the orthotopic site. In our models, single-cell whole-genome sequencing of primary and metastatic sites showed that distant metastases were most often the result of minor prevalence clones at the orthotopic site, suggesting that some metastatic phenotypes may be weakly negatively fit at the primary site. We validated the existence of a fitness hierarchy of copy number clones using a previously established paradigm of remixing and retransplanting clones. Single-cell clone analysis of competitive repopulation and re-emergence of metastases showed that CNAs arising in cancer evolution can mediate metastatic fitness. Moreover, some clones displaying strong metastatic tendency exhibited weaker survival at the primary site, consistent with the notion that metastatic phenotypes could have a fitness cost at the primary site. Finally, we conducted RNA-seq analysis combined with DriverNet analysis to dissect the contribution of CNA-mediated versus genome-independent transcriptional states. CNA mutations appeared to contribute strongly to transcriptional differences between clones. Among clones of high metastatic potential, we observed CNA-mediated and CNA-independent convergence on pathways such as epithelial-mesenchymal transition (EMT), established as mediators of metastatic cell survival at distant sites. Taken together, our data point to a contribution of CNA-mediated cancer evolution to metastatic states and identify distant-site context as a key determinant of CNA-mediated fitness.

cancer biology↗

bioRxiv2025

Modulating inter-mitochondrial contacts to increase membrane potential for mitigating blue light damage

Mitochondrial membrane potential (MMP) is essential for mitochondrial functions, yet current methods for modulating MMP lack precise spatial and temporal control. Here, we present an optogenetic system that enables reversible formation of inter-mitochondrial contacts (mito-contacts) with high spatiotemporal precision. Blue light stimulation induces rapid formation of mito-contacts, which fully dissipate upon cessation of illumination. These light-induced mito-contacts can enhance MMP, leading to increased ATP production under stress conditions. Moreover, in human retinal cells and C. elegans, high MMP induced by mito-contacts alleviates the deleterious effects of prolonged blue light exposure, restoring energy metabolism and extending organismal lifespan. This optogenetic approach provides a powerful tool for modulating MMP and offers potential therapeutic applications for diseases linked to mitochondrial dysfunction.

biophysics↗

bioRxiv2025

Mutational scanning reveals substrate-assisted autoregulation of the WNT destruction complex

The {beta}-catenin destruction complex (BDC) is a central node in WNT/{beta}-catenin signaling, governing embryonic development and adult tissue homeostasis. Although recognized as a prime therapeutic target in colorectal cancer (CRC) for three decades, its dynamic architecture and biochemical complexity have hindered mechanistic understanding. Here, we systematically mapped the sequence-function landscape of the BDC using tiled base editor screens across four endogenous components--CTNNB1, AXIN1, APC, and GSK3B. Validation studies identified [~]150 previously unreported mutations across these genes that affected WNT/{beta}-catenin signaling. In addition to known cancer-associated mutations, we discovered rare gain-of-function and separation-of-function alleles of AXIN1 and CTNNB1 that provide mechanistic insights into complex assembly and regulation. We describe a region in {beta}-catenin that regulates its binding to TCF/LEF transcription factors and demonstrate that the AXIN1-{beta}-catenin interface is critical for controlling signaling flux through the oncogenic BDC. Mechanistic studies revealed that assembly of the oncogenic BDC is scaffolded by its own substrate {beta}-catenin, establishing an autoregulatory mechanism that represents an unexploited vulnerability in cancers harboring common APC truncations. Our comprehensive mutational resource provides a foundation for understanding WNT/{beta}-catenin signaling mechanisms in health and disease, while revealing strategies for therapeutic intervention in WNT-driven cancers.

biochemistry↗

bioRxiv2025

The tuberculosis-associated microenvironment promotes HIV-1 persistence by impairing CD8+ T cell-mediated viral control

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is the most common coinfection in people living with HIV-1 (PLWH). This coinfection is associated with accelerated HIV-1 disease progression and reduced survival. However, the immunological and virological mechanisms driving this progression are incompletely understood. To address this knowledge gap, using pleural effusion samples from PLWH and TB, we investigated the HIV-1 genetic landscape and the anti-HIV-1 immune response impacted by a TB-associated microenvironment. Our results revealed an enrichment of genetically intact HIV-1 and impaired CD8+ T cell-mediated antiviral response at the site of HIV-1/Mtb coinfection. These findings indicate that the TB-associated microenvironment promotes the persistence of cells infected with replication-competent HIV-1 by creating a niche of reduced antiviral immune pressure, potentially contributing to the worsened clinical outcomes observed in PLWH and TB.

immunology↗

bioRxiv2025

Discovery of A Small Molecule non-IMiD Degrader of ZBTB7A for the Treatment of β-hemoglobinopathies

Sickle cell disease and {beta}-thalassemia, two major {beta}-hemoglobinopathies, pose significant clinical challenges globally. Current treatments often face limitations in efficacy and tolerability. The transcription factor ZBTB7A has emerged as a promising therapeutic target for reactivating fetal hemoglobin expression. Here, we report the discovery and characterization of SH6, a small molecule non-IMiD degrader of ZBTB7A. SH6 induces fetal hemoglobin in erythroid cell lines in a CRBN and ZBTB7A-dependent manner, and it is capable of inducing fetal hemoglobin expression in healthy donor, SCD and {beta}-thalassemia patient CD34+ cell derived erythroid cells. The efficacy of SH6 is confirmed in a xenotransplantation humanized mouse model. SH6 outperforms currently available therapeutic agents in vitro, and shows synergy with hypomethylating agents. SH6 exhibits a favorable in vivo toxicity profile. Our findings establish SH6 as a promising therapeutic lead candidate for further optimization towards clinical development for treatment of sickle cell disease and {beta}-thalassemia.

cell biology↗

bioRxiv2025

BRD2 Upregulation as a Pan-Cancer Adaptive Resistance Mechanism to BET Inhibition

Bromodomain and extraterminal motif (BET) inhibitors, such as JQ1, are promising cancer therapeutics that target epigenetic regulators, particularly BRD4. However, resistance to BET inhibitors (BETi) limits their clinical utility, necessitating a better understanding of adaptive mechanisms. We identified BRD2 upregulation as a conserved response to BET inhibition across multiple cancer types and hypothesized that BRD2 compensates for BRD4 loss, sustaining essential transcriptional programs upon treatment. Consistent with this, BRD2 knockdown sensitized cancer cells to BETi in vitro, and combining BRD2 depletion and JQ1 treatment significantly impaired tumor growth in vivo. At the chromatin level, BRD2 and BRD4 ChIP-seq analysis of pancreatic cancer cells showed consistent BRD4 loss from chromatin after JQ1 treatment, while BRD2 displacement differed by sensitivity. Resistant cells maintained higher BRD2 occupancy than sensitive cells, suggesting a link between BRD2 retention and drug response. Mechanistically, NFYA mediates BRD2 upregulation as NFYA depletion attenuated BRD2 upregulation upon BETi treatment. Collectively, our findings establish BRD2 as a critical mediator of pan-cancer adaptive resistance to BETi and identify NFYA as a novel transcriptional regulator of this process. Co-targeting BRD2 or its regulatory network offers a rational strategy to enhance the durability and efficacy of BET-based therapies.

cancer biology↗

bioRxiv2025

Huntington's disease LIG1 modifier variant increases ligase fidelity and suppresses somatic CAG repeat expansion

Huntingtons disease (HD) is a fatal neurodegenerative disorder caused by inheriting an expanded CAG repeat tract in the huntingtin gene (HTT) that further expands in somatic cells over an individuals lifetime. Genome-wide association studies have provided critical insight into factors that modify the course of disease. These include DNA repair genes that alter the rate of somatic expansion and other genes that do not appear to directly influence this process. One modifier gene is DNA ligase 1 (LIG1), in which a variant specifying a lysine to asparagine substitution (K845N) is associated with a profound (7-8 year) delay in the onset of motor signs. Here, we have taken a multifaceted approach to gain insight into the protective nature of this variant in HD. We demonstrate using in vitro ligase assays and enzyme kinetics that K845N enhances discrimination towards mismatched substrates and increases repair fidelity. Consistent with increased ligation fidelity, K845N confers protection against oxidative stress in cell-based assays. Finally, we demonstrate that the mouse LIG1 K843N orthologue suppresses somatic CAG expansion in HD knock-in mice. Overall, our data provide evidence that altered LIG1 function due to the K845N substitution may contribute to HD clinical delay by slowing somatic expansion in the brain and protecting the genome globally against damage. Significantly, our results provide a mechanistic foundation for considering DNA ligase fidelity as a therapeutic target in HD and potentially in other trinucleotide repeat disorders. Significance StatementWe analyzed a missense variant in DNA Ligase 1 (K845N) that is associated with a profound delay in the onset of Huntingtons disease (HD). We find that K845N enhances substrate discrimination towards mismatched substrates, thus increasing repair fidelity, conferring protection against oxidative stress and slows somatic expansion of the HD CAG repeat. Our observations provide insight into underlying mechanisms of disease modification and suggest avenues that can be harnessed for disease-modifying therapeutic intervention. Classification: Biological Sciences, Genetics

genetics↗

bioRxiv2025

WNK1 kinase activity is required for maintenance of podocyte structure

The filtration-function of glomeruli requires slit diaphragms formed by interdigitating podocyte foot processes, which are actin-based membrane protrusions. Dysregulation of mechanisms that maintain these membrane extensions lead to foot process effacement, proteinuria, and progression to chronic kidney disease. Building on our previous work that showed WNK1 kinase activity is necessary for the maintenance of normal biomechanical properties of glomeruli and podocyte foot process architecture, we tested the hypothesis that WNK1 kinase activity affects the structure of podocyte foot processes through modulation of actomyosin activity and focal adhesion complexes. Using a WNK1 kinase specific inhibitor, we determined by immunofluorescence microscopy of nascent focal adhesions, podocyte membrane spreading/extensions, and NMII paralog localization and extent of activation calculated from quantification of phosphorylated myosin, that all were sensitive to WNK1 kinase activity. Moreover, biochemical evidence of WNK1 kinase activity-dependent signalosomes supports a role for WNK1 in the maintenance of podocyte foot processes, and sarcomere-like structures (SLSs) that are induced in models of podocyte injury. Using primary and immortalized podocyte cell lines developed from control and Col4a3-/-Alport Syndrome model mice, we measured WNK1 kinase activity-dependent improvement in properties of injured podocytes in vitro. Physiological relevance of WNK1 kinase activity-dependent structural maintenance of podocyte foot processes was confirmed by significant acute proteinuria measured in response to WNK1 inhibition in vivo. Collectively, the results provide evidence that WNK1 kinase signalosome activity that includes formation of nascent focal adhesions and regulation of NMII localization and activity at membrane protrusions and extensions, are necessary for physiological maintenance of slit diaphragms. SignificanceTerminally differentiated podocytes are arborized cells with interdigitating foot processes that form the renal filtration barrier. Loss of foot process structural integrity causes progressive proteinuria, which can lead to irreversible renal injury, but the mechanisms that maintain foot process structure are incompletely understood. We report evidence that WNK1 kinase activity is required for maintenance of normal glomerular filtration in vivo, and this is mediated in part through WNK1 activity-dependent modulation of non-muscle myosin II activity, and formation of nascent focal adhesions that are necessary for lamellipodial extensions. Using glomeruli and podocyte cell lines developed from an Alport Syndrome podocyte injury model, we show that aspects of abnormal podocyte structure associated with chronic kidney disease can be suppressed through increased WNK1 activation.

cell biology↗

bioRxiv2025

fMRIPrep Lifespan: Extending A Robust Pipeline for Functional MRI Preprocessing to Developmental Neuroimaging

The adoption of a standardized preprocessing workflow is vital for fostering community, sharing, and reproducibility. fMRIPrep has been a critical advancement towards this end, however, it is limited in its capacity to be applied to data across the lifespan, starting from infancy. Here, we introduce fMRIPrep Lifespan, an extension of fMRIPrep that extends the standardized processing from childhood to senescence to include neonatal, infant, and toddler structural and functional MRI data preprocessing. This effort involves a NiPreps integration of 1) a workflow akin to fMRIPrep optimized for MRI data in the first years of life (previously NiBabies) and 2) upstream enhancements to the entire NiPreps suite, including multi-echo data processing, modularization of workflow components, and convergence of processing with other popular workflows (ABCD-BIDS, Human Connectome Project Pipelines). Using data from the Baby Connectome Project (participants 1-43 months of age), we demonstrate that fMRIPrep Lifespan produces high-quality outputs across a wide age range. Moving forward, the scalable, modular infrastructure of fMRIPrep Lifespan will ensure adaptability to data from birth to old age while maintaining robust and reproducible frameworks for functional MRI research across the lifespan.

bioinformatics↗

bioRxiv2025

H2O2-induced astrocytic collagen triggers neuronal death via fucosylation-dependent glial barrier formation upon ischemic stroke

The cascade of molecular and cellular events leading to neuronal death after a focal ischemic stroke remains enigmatic. Although astrocytes form glial barriers that may protect surrounding tissue, how barriers develop and contribute to neuronal death is unclear. Here, we show that H2O2 induces astrocytic type I collagen (COL1)-production via miR-29-mediated post-transcriptional and fucosylation-dependent post-translational regulations, leading to integrin activation and neuronal death. In photothrombosis (PT)-induced cortical stroke model, PT triggered H2O2-surge, astrogliosis, glial barrier formation, COL1 expression, fibrotic scarring, altered N-glycosylation, neuronal loss, and neurological deficits. Remarkably, these effects were reversed by astrocyte-specific COL1 or FUT8 gene-silencing or treatment with KDS12025, an H2O2-decomposing peroxidase enhancer. KDS12025s neuroprotective effects were also recapitulated in non-human primate stroke model. These findings delineate a previously unrecognized astrocyte-driven mechanism in which oxidative stress induces COL1 production, promoting neuronal death, and position H2O2 and astrocytic COL1 and FUT8 as promising therapeutic targets for ischemic stroke.

neuroscience↗

bioRxiv2025

Immune Composition of the Mononuclear Cell Fraction of Human Umbilical Cord Blood

Despite its therapeutic potential and unique immunological properties, the immune composition of umbilical cord blood lacks consistent and comprehensive characterizations. Human umbilical cord blood (UCB) is often discarded after delivery and is difficult to obtain for research purposes. Furthermore, most research on UCB is focused on properties of CD34+ hematopoietic stem cells for transplantation. The Binns Program for Cord Blood Research at Stanford University has the unique advantage of regular collection and isolation of mononuclear cells (MNC) from UCB donors. This study provides a robust characterization of the immune subset compositions of the CD34-negative MNC fraction of UCB (n=50). The study also compares the UCB data to adult peripheral blood (PB) mononuclear cells to identify differences in immune maturity. Using flow cytometry and single-cell RNA sequencing (scRNA-Seq), we analyzed UCB and adult PB MNC samples to characterize the cell surface protein and transcriptomic profiles of different immune subsets. Our study findings bring a higher-definition understanding of the unique immunological properties of umbilical cord blood. Study findings reveal a distinct immune profile in UCB, such as a higher average percentage of CD19 B Lymphocytes, CD4 T Cells, CD4 Naive T Cells, CD4 Recent Thymic Emigrants, CD8 Naive T Cells, CD8 Recent Thymic Emigrants, and CD19 Naive B Cells compared to adult PB. Additionally, there were fewer CD19 Memory B Cells in UCB compared to PB. The scRNA-Seq showed concordance in the proportion of immune cell types but captured more differentiated subtypes of cells. Additionally, scRNA-Seq showed unique clustering patterns in UCB, which reflect cell types that converge in adulthood as the immune system matures. These analyses yield the intriguing possibility that the immune heterogeneity of individuals at birth gives way to more stereotyped immune subsets as the immune system is exposed to the external environment and undergoes maturation. Overall, our findings provide a robust characterization of MNC UCB immune subsets and insights into how immune function develops from birth to adulthood.

immunology↗

bioRxiv2025

Solid tumor CAR T cells engineered with fusion proteins targeting PDL1 for localized IL-12 delivery

CAR T cell efficacy in solid tumors is limited due in part to the immunosuppressive TME. To improve anti-tumor responses, we hypothesized that enabling CAR T cells to secrete bifunctional fusion proteins consisting of a cytokine modifier (e.g., TGF{beta}trap, IL15, or IL12) combined with an immune checkpoint inhibitor (e.g., PDL1) will provide tumor localized immunomodulation to improve CAR T cell functionality. To that end, we engineered CAR T cells to secrete TGF{beta}trap, IL15, or IL12 molecules fused to PDL1 scFv, and assessed in vitro functionality and in vivo safety and efficacy in prostate and ovarian cancer models. CAR T cells engineered with PDL1-IL12 were superior in safety and efficacy compared to CAR T cells alone and to those engineered with PDL1 fused with TGF{beta}trap or IL15. Further, PDL1-IL12 engineered CAR T cells improved T cell trafficking and tumor infiltration, localized IFN{gamma} production, TME modulation, and anti-tumor responses, with reduced systemic inflammation-associated toxicities. We believe our PDL1-IL12 engineering strategy presents an opportunity to improve CAR T cell clinical efficacy and safety across multiple solid tumor types.

bioengineering↗