A5023083194- Cancer Immunotherapy and Biomarkers
- Immunotherapy and Immune Responses
- Immune cells in cancer
- interferon and immune responses
- Neuroblastoma Research and Treatments
- Immune Cell Function and Interaction
- Glioma Diagnosis and Treatment
- Cancer Research and Treatments
- Nanoplatforms for cancer theranostics
- Single-cell and spatial transcriptomics
- Cytokine Signaling Pathways and Interactions
- T-cell and B-cell Immunology
- Ferroptosis and cancer prognosis
- CAR-T cell therapy research
- Immunodeficiency and Autoimmune Disorders
- Diabetes and associated disorders
- Neuroinflammation and Neurodegeneration Mechanisms
- Cancer, Hypoxia, and Metabolism
- Mast cells and histamine
- Cell Adhesion Molecules Research
- Renal Diseases and Glomerulopathies
- Brain Metastases and Treatment
- Cell Image Analysis Techniques
- Liver Disease Diagnosis and Treatment
- Extracellular vesicles in disease
Vanderbilt University Medical Center
2019-2024
Vanderbilt University
2019-2024
Nashville Oncology Associates
2023
Massachusetts General Hospital
2023
Breast Cancer Research Foundation
2023
Vanderbilt-Ingram Cancer Center
2023
Bipar
2023
The University of Texas MD Anderson Cancer Center
2012-2020
The University of Texas Health Science Center at Houston
2010-2020
The University of Texas at Austin
2011-2015
Despite the success of immune checkpoint blockade against melanoma, many "cold" tumors like prostate cancer remain unresponsive. We found that hypoxic zones were prevalent across preclinical and resisted T cell infiltration even in context CTLA-4 PD-1 blockade. demonstrated hypoxia-activated prodrug TH-302 reduces or eliminates hypoxia these tumors. Combination therapy with this hypoxia-prodrug cooperated to cure more than 80% transgenic adenocarcinoma mouse prostate-derived (TRAMP-derived)...
Coordinated manipulation of independent immune regulatory pathways in the tumor microenvironment-including blockade T-cell checkpoint receptors and reversal suppressive myeloid programs-can render aggressive cancers susceptible to rejection. Elevated toxicity associated with combination immunotherapy, however, prevents translation most efficacious regimens. We evaluated checkpoint-modulating antibodies targeting CTLA-4, PD-1, 4-1BB together agonists either STING or Flt3 TRAMP-C2 model...
Significance Nearly all cervical, anal, vulvar, and penile cancer up to half of oropharyngeal cancers are driven by the E6 E7 oncoproteins human papilloma virus (HPV). Therapeutic vaccination against these HPV proteins can slow disease progression in animal models patients, but is rarely curative. We demonstrate that coadministration agonist antibodies targeting T-cell costimulatory receptor 4-1BB an intranasal E6/E7 peptide vaccine promoted durable regression 100% animals bearing + TC-1...
Abstract Purpose: Agonist antibodies targeting the T-cell costimulatory receptor 4-1BB (CD137) are among most effective immunotherapeutic agents across preclinical cancer models. In clinic, however, development of these has been hampered by dose-limiting liver toxicity. Lack knowledge mechanisms underlying this toxicity limited potential to separate agonist–driven tumor immunity from hepatotoxicity. Experimental Design: The capacity agonist induce was investigated in immunocompetent mice,...
Abstract Despite the clinical success of T-cell checkpoint blockade, most patients with cancer still fail to have durable responses immunotherapy. The molecular mechanisms driving blockade resistance, whether preexisting or evolved, remain unclear. To address this critical knowledge gap, we treated B16 melanoma combination CTLA-4, PD-1, and PD-L1 a Flt3 ligand vaccine (≥75% curative), isolated tumors resistant therapy, serially passaged them in vivo same treatment regimen until they...
A fluorescence-based, high-resolution imaging approach was used to visualize longitudinally the cellular events unfolding during T cell-mediated tumor destruction. The dynamic interplay of cells, cancer antigen loss variants, and stromal cells—all color-coded in vivo—was analyzed established, solid tumors that had developed behind windows implanted on backs mice. Events could be followed repeatedly within precisely same region—before, after adoptive cell therapy—thereby enabling for first...
Radiographic contact of glioblastoma (GBM) tumors with the lateral ventricle and adjacent stem cell niche correlates poor patient prognosis, but cellular basis this difference is unclear. Here, we reveal functionally characterize distinct immune microenvironments that predominate in subtypes GBM distinguished by proximity to ventricle. Mass cytometry analysis isocitrate dehydrogenase wild-type human identified elevated T checkpoint receptor expression greater abundance a specific...
Meeting abstracts Tumor hypoxia predicts poor outcomes across all cancers and has long been recognized as a critical source of resistance to both chemotherapy radiotherapy. Despite the success T cell immune checkpoint blockade in treating melanoma, aggressive adenocarcinomas prostate
The idiopathic inflammatory myopathies (IIM) are a rare clinically heterogeneous group of conditions affecting the skin, muscle, joint, and lung in various combinations. While myositis specific autoantibodies well described, we postulate that broader immune endotypes exist IIM spanning B cell, T monocyte compartments. This study aims to identify through detailed immunophenotyping peripheral blood mononuclear cells (PBMCs) patients compared healthy controls. We collected PBMCs from 17 with...
<i>Background:</i> Glomerular fibrosis is the common end result of glomerulonephritis (GN) regardless etiology. In our rat model for anti-glomerular basement membrane GN, severe follows glomerular inflammation. We investigated association between expression extracellular matrix (ECM) proteins and progression fibrosis. <i>Methods:</i> Expression ECM genes in glomeruli was determined at RNA protein levels. Immunofluorescence applied to identify cell sources molecules....
In our rat model for anti-GBM GN, severe fibrosis follows glomerular inflammation. A potential role of extracellular matrix protein osteopontin (OPN) in was investigated.Neutralizing OPN antiserum or control normal serum injected into the experimental rats at late inflammatory/early fibrotic stage. Glomerular inflammation and were determined.OPN treatment had little effect on However, resulted a significant reduction number glomeruli (50% controls). Histology observation showed that tissue...
### P189 Rational combinations of intratumoral T cell and myeloid agonists mobilize abscopal responses in prostate cancer #### Casey Ager1, Matthew Reilley2, Courtney Nicholas1, Todd Bartkowiak1, Ashvin Jaiswal1, Michael Curran1 ##### 1Department Immunology, University Texas MD Anderson
Cyclic immunohistochemistry (cycIHC) uses sequential rounds of colorimetric immunostaining and imaging for quantitative mapping location number cells interest. Additionally, cycIHC benefits from the speed simplicity brightfield microscopy, making collection entire tissue sections slides possible at a trivial cost compared to other high dimensional modalities. However, large datasets currently require an expert data scientist concatenate separate open-source tools each step image...
Abstract Patients with STAT1 gain-of-function (GOF) pathogenic variants have enhanced or prolonged phosphorylation following cytokine stimulation and exhibit increased yet heterogeneous susceptibility to infections, autoimmunity, cancer. Although disease phenotypes are diverse other genetic factors contribute, how GOF affects sensitivity cell biology remains poorly defined. In this study, we analyzed the immune immunometabolic profiles of two patients known heterozygous mutation variants. A...
Many types of glomerulonephritis (GN) undergo tandem connected phases: inflammation and fibrosis. Fibrosis in human GNs leads to irreversible end-stage disease. This study investigated how these 2 phases were controlled.
<i>Background/Aims:</i> In an antiglomerular basement membrane glomerulonephritis (GN) model, GN-resistant Lewis (LEW) rats naturally recover from early glomerular inflammation (days 21–23). We have previously identified a glomeruli-infiltrating CD8α<sup>+</sup>CD11<sup>high</sup>MHC II<sup>+</sup> cell (GIL CD8α<sup>+</sup> cell) in GN-prone Wistar Kyoto (WKY) rats, which terminates through inducing T apoptosis prior to fibrosis at...
Abstract Agonist antibodies against the T cell costimulatory receptor 4-1BB have proven extraordinarily efficacious in treatment of a multitude pre-clinical murine tumors both mono- and combination therapy settings. Although administration α4-1BB Phase I II clinical trials has led to disease stabilization partial remission some cases melanoma; high grade, dose limiting liver inflammation slowed progress these agents toward FDA approval. We sought uncover mechanisms by which agonist trigger...
Abstract The transcription factor FOXN1 plays an established role in thymic epithelial development to mediate selection of maturing thymocytes. Patients with heterozygous loss-of-function variants are associated T cell lymphopenia at birth and low TCR excision circles that can ultimately recover. Although CD4+ reconstitution these patients is not completely understood, a lower proportion naive cells adults has suggested for homeostatic proliferation. In this study, we present...
Abstract Antibody modulation of T cell co-inhibitory (e.g. CTLA-4) or co-stimulatory 4-1BB) receptors promotes clinical responses to a variety cancers. Therapeutic cancer vaccination, in contrast, has produced limited benefit. The E6 and E7 onco-proteins human papilloma virus drive the majority genital oropharyngeal We discovered 15-19 amino acid peptides from HPV16 E6/E7 for which immunity correlates with disease-free survival patients treated high-grade cervical neoplasia. report that...
Abstract Advances in our understanding of tumor immune biology and development cancer immunotherapies have led to improved outcomes for patients who suffer from aggressive cancers such as melanoma. Despite the clinical success checkpoint blockade, a majority still fail respond, underlying mechanisms that drive resistance remain unclear. To understand why subset tumors respond immunotherapy, we established novel murine model melanoma is fully resistant blockade. By vivo passaging...
Abstract Cyclic immunohistochemistry (cycIHC) uses sequential rounds of colorimetric immunostaining and imaging for quantitative mapping location number cells interest. In addition, cycIHC benefits from the speed simplicity brightfield microscopy data collection, making collection entire tissue sections slides possible at a trivial cost compared to other high dimensional modalities. However, large datasets (greater than 50 GB) currently require an expert scientist concatenate separate...