Biology subjects

Travis, K.

Publications and source records attributed to Travis, K..

5 recordsLinked to original sources

bioRxiv2026

Targeting alpha-ketoglutarate starvation within the tumor-immune microenvironment rescues T cell effector function in cancer immunotherapy

Given its status as the leading cause of global cancer mortality, there is a critical need to enhance immunotherapy strategies for lung cancer to overcome widespread resistance to current treatments. Immunotherapy recruits the patient's immune system to attack and destroy cancer cells. While highly effective in a subset of patients, chronic exposure of immune cells to cancer cells leads to a progressive loss of effector T cell function and progression of T cell exhaustion; now considered two well-established hallmarks of immunotherapy resistance. The tumor-immune microenvironment (TIME)-driven differentiation into the exhausted T cell phenotype is marked by a loss of metabolic plasticity and epigenome-wide changes in distribution of repressive histone marks such as histone H3 subunit methylation at lysine 27 (H3K27me3). Here, we studied how these processes are connected to metabolite availability within the TIME. In vitro, chronic antigen stimulation and hypoxia led to rapid loss of effector function, associated with a suppression of alpha-ketoglutarate (aKG) intracellular concentrations in T cells. Supplementation of cell-permeable aKG led to a rescue of effector cytokine production and to improved cytotoxic capacity despite chronic antigen stimulation and hypoxia. Increased intracellular aKG levels restored the activity of H3K27 demethylases UTX and JMJD3, consistent with epigenome-wide decreased H3K27me3. In vivo, dietary supplementation with commercially available calcium-aKG (Ca-aKG) supplements led to an elevation of serum and intratumoral aKG levels associated with a significant increase of immunotherapy effectiveness in mouse models of NSCLC. Clinical samples from patients with NSCLC contained significantly decreased serum aKG levels in older NSCLC patients (>65 years of age). Analysis identified a novel association between serum aKG levels and poor immunotherapy response. Thus, our work demonstrates that intratumoral metabolite starvation can be therapeutically exploited to improve immunotherapy outcomes in non-small cell lung cancer (NSCLC).

cancer biology↗

bioRxiv2026

Mitochondrial Oxygen Consumption Drives Lung Tumor Hypoxia and Resistance to Therapy via Copy Number Alteration in Mitochondrial Electron Transport Subunit NDUFB5

Decades of research have shown that tumor hypoxia is associated with resistance to anti-cancer treatments. Analysis of TCGA gene expression profiles indicates that NSCLC is among the most hypoxic of cancers despite the high levels of oxygen in the surrounding lung tissue. Several groups have shown that extrinsic factors such as poorly formed tumor vascular contributes to tumor hypoxia. Here, we have investigated the possibility that genetic abnormalities within the tumor also contribute to the development of hypoxia. Our analysis of NSCLC patient datasets in the Cancer Genome Atlas (TCGA) PanCancer and ORIEN datasets revealed a strong correlation between tumor hypoxia and amplification of chromosome 3q which is found in up to 40% of NSCLC. Several oncogenic driver genes have been identified in 3q, and we identified a passenger gene encoding mitochondrial complex I subunit NDUFB5 at 3q26.33. To provide experimental evidence that NDUFB5 amplification can drive tumor hypoxia, we have used CRISPR activation technology to generate murine cells overexpressing the endogenous NDUFB5 gene. We found that cells overexpressing NDUFB5 have elevated rates of oxygen consumption, and tumors grown from these cells have increased amounts of hypoxia with associated treatment resistance. Here, we investigate the impact of manipulating NDUFB5 gene expression on mitochondrial complex I activity and experimentally validate the clinical observations that NDUFB5 overexpression leads to increased levels of intratumoral hypoxia and increased resistance to radiation therapy and immunotherapy.

cancer biology↗

bioRxiv2025

Mouse Models Uniformly Featuring Human-like Lesions Harboring Drug-tolerant Mycobacterium tuberculosis

Mouse models have been key to studies of tuberculosis pathogenesis and drug efficacy, but many, such as those employing BALB/c mice, fail to reproduce the full range of heterogenous microniches observed in well-structured human lesions, which feature hypoxic caseous cores of necrotic debris surrounded by infected foamy macrophages. The granuloma presents a variety of environments differing in levels of oxygen, ions, nutrients, and intra versus extracellular residence, which determine the physiological state of the infecting bacillus and its susceptibility to immune or drug control. Recently, alternative mouse strains such as C3HeB/FeJ have allowed the study of infection and treatment in the context of these varied environments but exhibit substantial inconsistency in development of human-like lesions, both within and between individual mice. Building on the observation that inducible nitric oxide synthase (Nos2)-deficient mice consistently develop hypoxic necrotic lesions, we have established two simplified models with infection by the aerosol route. The first uses the slightly attenuated M. tuberculosis R1Rv strain, which produces a progressive infection that is contained at a high stable burden by an adaptive immune response. In the second model, vaccination with the attenuated {Delta}RD1, pantothenate auxotroph mc2 6230 protects from an otherwise lethal infection with virulent M. tuberculosis Erdman. This model reflects most contemporary tuberculosis infections, which take place in the context of a pre-existing immune response from vaccination. Both variations uniformly develop well-structured hypoxic necrotic lesions harboring drug tolerant bacteria. These refined models will be useful in studies of M. tuberculosis infection and treatment.

microbiology↗

bioRxiv2025

Anti-Parkinsonian Drugs Rescue Locomotor Deficits in JIP3 Knockout Zebrafish: Implications for Treating Patients with MAPK8IP3-related Neurodevelopmental Disorders

MAPK8IP3-related neurodevelopmental disorders are a spectrum of rare conditions caused by de novo mutations in the MAPK8IP3 gene that encodes the JIP3 protein. These disorders are associated with a spectrum of neurodevelopmental symptoms that manifest in children and cause brain abnormalities, profound intellectual disabilities, movement disorders, and developmental delays. JIP3 is required for axonal transport of proteins and organelles between the soma and the synaptic terminal of neurons, a process critical for normal brain development and function. Homozygous loss-of-function mutations in JIP3 lead to impaired axonal transport and aggregation of cargo, which result in axonal swelling and stunted elongation. Despite these severe outcomes, disease mechanisms are poorly understood, and no current treatments are available. Here we conduct thorough morphological, behavioral, and motility phenotyping in the JIP3 knockout zebrafish and identify locomotor deficits and morphological abnormalities. To identify treatment options, we used insights from expert clinicians and the artificial intelligence tool, mediKanren, to identify drug candidates hypothesized to improve patient symptoms or compensate for the loss of JIP3 at the molecular level. We then prioritized drugs that are FDA-approved, safe for children, and readily available. These collective efforts identified amantadine and levodopa as candidate therapies and rescued motor phenotypes associated with JIP3 loss-of-function in zebrafish.

neuroscience↗

bioRxiv2024

Characterization of Collaborative Cross mouse founder strain CAST/EiJ as a novel model for lethal COVID-19

Mutations in SARS-CoV-2 variants of concern (VOCs) have expanded the viral host range beyond primates, and a limited range of other mammals, to mice, affording the opportunity to exploit genetically diverse mouse panels to model the broad range of responses to infection in patient populations. Here we surveyed responses to VOC infection in genetically diverse Collaborative Cross (CC) founder strains. Infection of wild-derived CC founder strains produced a broad range of viral burden, disease susceptibility and survival, whereas most other strains were resistant to disease despite measurable lung viral titers. In particular, CAST/EiJ, a wild-derived strain, developed high lung viral burdens, more severe lung pathology than seen in other CC strains, and a dysregulated cytokine profile resulting in morbidity and mortality. These inbred mouse strains may serve as a valuable platform to evaluate therapeutic countermeasures against severe COVID-19 and other coronavirus pandemics in the future.

immunology↗