A5058978735- Cancer Immunotherapy and Biomarkers
- Immune Cell Function and Interaction
- Cancer Mechanisms and Therapy
- Pancreatic and Hepatic Oncology Research
- Immunotherapy and Immune Responses
- CAR-T cell therapy research
- Peroxisome Proliferator-Activated Receptors
- Axon Guidance and Neuronal Signaling
- Immune cells in cancer
- Cancer, Lipids, and Metabolism
- Lymphoma Diagnosis and Treatment
- Chromatography in Natural Products
- Angiogenesis and VEGF in Cancer
- Cancer Cells and Metastasis
- RNA modifications and cancer
- Cytokine Signaling Pathways and Interactions
- Inflammatory mediators and NSAID effects
- Cell Image Analysis Techniques
- Lung Cancer Research Studies
- Cancer, Stress, Anesthesia, and Immune Response
- Fatty Acid Research and Health
- Adipose Tissue and Metabolism
- T-cell and B-cell Immunology
- Complement system in diseases
- AI in cancer detection
University of Colorado Anschutz Medical Campus
2021-2025
University of Colorado Denver
2020-2024
University of Colorado Boulder
2019
DiscoveRx (United States)
2014
Abstract In the setting of conventional radiation therapy, even when combined with immunotherapy, head and neck cancer often recurs locally regionally. Elective nodal irradiation (ENI) is commonly employed to decrease regional recurrence. Given our developing understanding that immune cells are radio-sensitive, T cell priming occurs in draining lymph nodes (DLNs), we hypothesize therapy directed at primary tumor only will increase effectiveness immunotherapies. We find ENI increases local,...
In pancreatic ductal adenocarcinoma (PDAC) patients, we show that response to radiation therapy (RT) is characterized by increased IL-2Rβ and IL-2Rγ along with decreased IL-2Rα expression. The bispecific PD1-IL2v a PD-1-targeted IL-2 variant (IL-2v) immunocytokine engineered cis targeted PD-1 abolished binding, which enhances tumor-antigen-specific T cell activation while reducing regulatory (Treg) suppression. Using in orthotopic PDAC KPC-driven tumor models, marked improvement local...
Background Numerous trials combining radiation therapy (RT) and immunotherapy in head neck squamous cell carcinoma (HNSCC) are failing. Using preclinical immune cold models of HNSCC resistant to RT-immune checkpoint inhibitors, we investigate therapeutic approaches overcoming such resistance by examining the differential microenvironmental response RT. Methods We subjected two HPV-negative orthotopic mouse combination RT, regulatory T cells (Treg) depletion, and/or CD137 agonism. Tumor...
Metastasis remains a major hurdle in treating aggressive malignancies such as pancreatic ductal adenocarcinoma (PDAC). Improving response to treatment, therefore, requires more detailed characterization of the cellular populations involved controlling metastatic burden.PDAC patient tissue samples were subjected RNA sequencing analysis identify changes immune infiltration following radiotherapy. Genetically engineered mouse strains combination with orthotopic tumor models PDAC used...
Background Treatment with immunotherapy can elicit varying responses across cancer types, and the mechanistic underpinnings that contribute to response vrsus progression remain poorly understood. However, date there are few preclinical models accurately represent these disparate disease scenarios. Methods Using combinatorial radio-immunotherapy consisting of PD-1 blockade, IL2Rβγ biased signaling, OX40 agonism we were able generate tumor conflicting responses, where head neck squamous cell...
Abstract Differential outcomes of EphB4-ephrinB2 signaling offers formidable challenge for the development cancer therapeutics. Here, we interrogate effects targeting EphB4 and ephrinB2 in head neck squamous cell carcinoma (HNSCC) within its microenvironment using genetically engineered mice, recombinant constructs, pharmacologic agonists antagonists. We observe that manipulating intracellular domain on cells accelerates tumor growth angiogenesis. loss also triggers compensatory upregulation...
Natural killer (NK) cells are type I innate lymphoid that known for their role in killing virally infected or cancer through direct cytotoxicity. In addition to tumor cell killing, NK play fundamental roles the microenvironment secretion of key cytokines, such as FMS-like tyrosine kinase 3 ligand (FLT3L). Although radiotherapy is mainstay treatment most cancers, on not well characterized.
Resistance to therapy is a major problem in treating head and neck squamous cell carcinomas (HNSCC). Complement system inhibition has been shown reduce tumor growth, metastasis, therapeutic resistance other models, but yet be explored the context of HNSCC. Here, we tested effects complement its potential We conducted our studies using two Human Papilloma Virus (HPV)-negative HNSCC orthotopic mouse models. C3aR C5aR1 receptor antagonists were paired with radiation (RT). Tumor growth was...
Abstract Purpose: Head and neck cancer (HNC) improvements are stagnant, even with advances in immunotherapy. Our previous clinical trial data show that altered fatty acid (FA) metabolism correlates outcome. We hypothesized pharmacologic dietary modulation of FA catabolism will affect therapeutic efficacy. Experimental Design: performed vivo vitro experiments using PPARα agonism fenofibrate (FF) or high oleic diets (OAD) radiotherapy, generating metabolomic, proteomic, stable isotope tracing,...
Clinically approved head and neck squamous cell carcinoma (HNSCC) immunotherapies manipulate the immune checkpoint blockade (ICB) axis but have had limited success outside of recurrent/metastatic disease. Interleukin-7 (IL7) has been shown to be essential for effector T-cell survival, activation, proliferation. Here, we show that IL7 in combination with radiotherapy (RT) is effective activating CD8 + T-cells reducing tumor growth. Our studies were conducted using both human papillomavirus...
Abstract The aggressive nature of glioblastoma multiforme (GBM) may be attributed to the dysregulation pathways driving both proliferation and invasion. EphrinB2, a membrane‐bound ligand for some Eph receptors, has emerged as critical target regulating these pathways. In this study, we investigated role ephrinB2 in invasion GBM using intracranial subcutaneous xenograft models. Cancer Genome Atlas analysis suggested high transcript low methylation levels poor prognostic indicators GBM,...
The C. elegans aminophospholipid translocase TAT–1 maintains phosphatidylserine (PS) asymmetry in the plasma membrane and regulates endocytic transport. Despite these important functions, structure-function relationship of this protein is poorly understood. Taking advantage tat-1 mutations identified by million mutation project, we investigated effects 16 single amino-acid substitutions on two functions protein. Two that alter a highly conserved PISL motif fourth transmembrane domain DKTGT...
STAT3 signaling has been shown to regulate cellular function and cytokine production in the tumor microenvironment (TME). Within head neck squamous cell carcinoma (HNSCC) TME, we previously showed that therapeutic targeting of combination with radiation resulted improved growth delay. However, given independent regulatory effects on anti-tumor immunity, aimed decipher individually cancer cell, T cells (Tregs), natural killer (NK) compartments driving resistance therapy HNSCCs. We utilized a...
Abstract Animal experiments are often used to determine effects of drugs and other biological conditions on cancer progression, but poor accuracy reproducibility established tumor measurement methods make results unreliable. In orthotopic mouse models head neck cancer, volumes approximated from caliper measurements conventionally compare groups, geometrical challenges the procedure imprecise. To address this, we developed software better measure these tumors by automated analysis cone-beam...
Abstract Head and Neck Squamous Cell Carcinoma (HNSCC) is a deadly cancer with poor response to targeted therapy, largely driven by an immunosuppressive tumor microenvironment (TME). Here we examine the immune-modulatory role of receptor tyrosine kinase EphA4 in HNSCC progression. Within TME, primarily expressed on regulatory T cells (Tregs) macrophages. In contrast ephrinB2, activating ligand EphA4, blood vessels. Using genetically engineered mouse models, show that Tregs promotes growth,...
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<div>AbstractPurpose:<p>Head and neck cancer (HNC) improvements are stagnant, even with advances in immunotherapy. Our previous clinical trial data show that altered fatty acid (FA) metabolism correlates outcome. We hypothesized pharmacologic dietary modulation of FA catabolism will affect therapeutic efficacy.</p>Experimental Design:<p>We performed <i>in vivo</i> vitro</i> experiments using PPARα agonism fenofibrate (FF) or high oleic diets (OAD)...
<div>AbstractPurpose:<p>Head and neck cancer (HNC) improvements are stagnant, even with advances in immunotherapy. Our previous clinical trial data show that altered fatty acid (FA) metabolism correlates outcome. We hypothesized pharmacologic dietary modulation of FA catabolism will affect therapeutic efficacy.</p>Experimental Design:<p>We performed <i>in vivo</i> vitro</i> experiments using PPARα agonism fenofibrate (FF) or high oleic diets (OAD)...
The EphB4-ephrinB2 signaling axis has been heavily implicated in metastasis across numerous cancer types. Our emerging understanding of the dichotomous roles that EphB4 and ephrinB2 play head neck squamous cell carcinoma (HNSCC) poses a significant challenge to rational drug design. We find knockdown cells enhances preclinical HNSCC models by augmenting immunosuppressive like T regulatory (Tregs) within tumor microenvironment. inhibition also amplifies their ability metastasize through...
Abstract Background Treatment with immunotherapy can elicit varying responses across cancer types, and the mechanistic underpinnings that contribute to response vs. progression remain poorly understood. However, date there are few preclinical models accurately represent these disparate disease scenarios. Methods Using combinatorial radio-immunotherapy consisting of PD-1 blockade, IL2Rβγ biased signaling, OX40 agonism we were able generate tumor conflicting responses, where head neck squamous...
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