A5070956012- CAR-T cell therapy research
- Immune Cell Function and Interaction
- Immunotherapy and Immune Responses
- Cancer Immunotherapy and Biomarkers
- T-cell and B-cell Immunology
- Chemokine receptors and signaling
- Heme Oxygenase-1 and Carbon Monoxide
- Adipokines, Inflammation, and Metabolic Diseases
- Virus-based gene therapy research
- Diet, Metabolism, and Disease
- Monoclonal and Polyclonal Antibodies Research
- Retinoids in leukemia and cellular processes
- Adipose Tissue and Metabolism
- Cell Adhesion Molecules Research
- Genetics and Neurodevelopmental Disorders
- IL-33, ST2, and ILC Pathways
- Immune Response and Inflammation
- Nuclear Receptors and Signaling
- Glycosylation and Glycoproteins Research
- Antioxidant Activity and Oxidative Stress
- Cancer, Lipids, and Metabolism
- Alcohol Consumption and Health Effects
- Hepatocellular Carcinoma Treatment and Prognosis
- NF-κB Signaling Pathways
- Autism Spectrum Disorder Research
Saint Louis University
2012-2024
UNC Lineberger Comprehensive Cancer Center
2016-2023
Saint Louis University
2023
National Cancer Institute
2017-2022
UCLouvain Saint-Louis Brussels
2013
Fred Hutch Cancer Center
2004-2012
Juntendo University
2012
University of Washington
2004-2012
Seattle University
2006
University of Kansas
1999-2004
Loss-of-function mutations or abnormal expression of the X-linked gene encoding methyl CpG binding protein 2 (MeCP2) cause a spectrum postnatal neurodevelopmental disorders including Rett syndrome (RTT), nonsyndromic mental retardation, learning disability, and autism. Mice expressing truncated allele Mecp2 ( 308 ) reproduce motor social behavior abnormalities RTT; however, it is not known whether deficits are present in these animals. We investigated memory, neuronal morphology, synaptic...
Abstract Obesity is a well-established risk factor for human cancer, yet the underlying mechanisms remain elusive. Immune dysfunction commonly associated with obesity but whether compromised immune surveillance contributes to cancer susceptibility in individuals unclear. Here we use mouse model of diet-induced investigate tumor-infiltrating CD8 + T cell responses lean, obese, and previously obese hosts that lost weight through either dietary restriction or treatment semaglutide. While both...
Rett syndrome (RTT) is an autistic spectrum disorder with a known genetic basis. RTT caused by loss of function mutations in the X-linked gene MECP2 and characterized acquired motor, social language skills females beginning at 6–18 months age. also cause non-syndromic mental retardation males females, abnormalities MeCP2 expression brain have been found disorders. We studied home-cage behavior interactions mouse model (Mecp2308/Y) carrying mutation similar to common causing alleles. Young...
Immune responses generated against malignant cells have the potential to inhibit tumor growth, or even eliminate transformed before a forms. However, immune tolerance mechanisms that normally protect healthy tissues from autoimmune damage pose formidable barrier development of effective anti-tumor immunity. Because are derived self-tissues, majority defined antigens either shared aberrantly expressed self-proteins. Eliciting productive T cell such proteins is challenging, as most...
Spontaneous antigen-specific T cell responses can be generated in hosts harboring a variety of solid malignancies, but are subverted by immune evasion mechanisms active within the tumor microenvironment. In contrast to tumors, that regulate activation versus tolerance hematological malignancies have been underexplored. A murine acute myeloid leukemia (AML) model was used investigate against AML cells inoculated i.v. s.c. Robust were after s.c., not i.v., inoculation. fact, inoculation...
Abstract The ability to regulate ongoing inflammation using regulatory T cells (Tregs) is under intense investigation. Strategies induce and expand Ag-specific Tregs are being developed, whether various types of suppressive in the inflammatory conditions associated with disease needs be determined. In this study, we report that TGF-β–induced (iTregs) expanded specific for a major self-Ag autoimmune gastritis suppress pathology when administered late process disease. Transferred iTregs...
Abstract Tolerizing mechanisms within the host and tumor microenvironment inhibit T-cell effector functions that can control cancer. These blunt adoptive immunotherapy with infused T-cells due to a complex array of signals determine tolerance, survival, or deletion. Ligation negative regulatory receptors CTLA4, PD-1(PDCD1), LAG3 on normally hinders their response antigen through nonredundant biochemical processes interfere stimulatory pathways. In this study, we used an established mouse...
Antitumor immunity is impaired in obese mice. Mechanistic insight into this observation remains sparse and whether it recapitulated patients with cancer unclear because clinical studies have produced conflicting controversial findings. We addressed by analyzing data from a diverse array of types. found that survival after immunotherapy was not accurately predicted body mass index or serum leptin concentrations. However, oxidized low-density lipoprotein (ox-LDL) identified as suppressor...
Adoptive T-cell immunotherapy has shown promise in the treatment of human malignancies, but challenge isolating T cells with high avidity for tumor antigens each patient limited application this approach. The transfer into receptor (TCR) genes encoding high-affinity TCRs recognizing defined tumor-associated can potentially circumvent obstacle. Using a well-characterized murine model adoptive widely disseminated leukemia, we demonstrate that TCR gene-modified cure mice tumor. One goal such...
Coinhibitory receptor blockade is a promising strategy to boost T-cell immunity against variety of human cancers. However, many patients still do not benefit from this treatment, and responders often experience immune-related toxicities. These issues highlight the need for advanced mechanistic understanding improve patient outcomes uncover clinically relevant biomarkers treatment efficacy. T-cell-intrinsic signaling pathways engaged during checkpoint are well defined, particularly...
Checkpoint blockade immunotherapy relies on the empowerment of immune system to fight cancer. Why some patients fail achieve durable clinical responses is not well understood, but unique individual factors such as diet, obesity, and related metabolic syndrome could play a role. The link between obesity patient outcomes remains controversial has been mired by conflicting reports limited mechanistic insight. We addressed this in C57BL/6 mouse model diet-induced using Western diet high both...
Abstract Emerging evidence in preclinical models demonstrates that antitumor immunity is not equivalent between males and females. However, more investigation patients across a wider range of cancer types needed to fully understand sex as variable tumor immune responses. We investigated differences T-cell responses male female with lung by performing sex-based analysis single cell transcriptomic datasets. found the transcript encoding CXC motif chemokine ligand 13 (CXCL13), which has...
Establishing peripheral CD8+ T cell tolerance is vital to avoid immune mediated destruction of healthy self-tissues. However, it also poses a major impediment tumor immunity since tumors are derived from self-tissue and often induce dysfunction. Thus, understanding the mechanisms that regulate versus has important implications for human health. Signals received tissue environment largely dictate whether responding cells become activated or tolerant. For example, induced expression subsequent...
Cross-presentation of normal self and candidate tumor Ags by bone marrow (BM)-derived APCs that have not been activated has demonstrated as a major mechanism contributing to acquisition tolerance mature T cells first encounter an Ag in the periphery (cross-tolerance). Following adoptive transfer naive TCR-transgenic CD8(+) into host expressing transgenic is potentially targetable hepatocytes self-Ag, we found majority Ag-specific were deleted, with remaining rendered anergic. Studies BM...
Strategies to boost the numbers and functions of regulatory T cells (Tregs) are currently being tested as means treat autoimmunity. While Tregs have been shown be effective in this role, strategies manipulate effectively suppress later stages ongoing diseases need established. In study, we evaluated ability TGF-β-induced (iTregs) specific for major self-antigen autoimmune gastritis established mice. When transferred into mice during disease, iTregs demethylated Foxp3 promoter, maintained...
Interleukin-2 (IL2) was among the earliest reagents used for cancer immunotherapy due to its ability support survival and function of tumor-reactive T cells. However, treatment with IL2 is accompanied by off-target toxicity low response rates in patients. In mouse models, these issues are largely overcome when administered as a cytokine/antibody complex (IL2c). The has longer serum half-life can be designed preferential cytokine delivery specific cells interest. Early studies showed IL2c...
During chronic viral infections, responses by virus-specific CD8+ T cells become marginalized the acquisition of functional defects and reduced cell numbers in a process defined as exhaustion. Similarly, tolerance to self-antigen is also characterized impaired effector function eventual deletion self-reactive cells. Induction both exhaustion involve many shared inhibitory mechanisms, thus similar therapeutic approaches have proven effective these distinct environments. We previously...
Abstract Major gains in the efficacy of T cell-based therapies for cancer and infectious diseases could be realized through improved understanding signals that control expansion differentiation CD8+ cytolytic cells. IL-2, IL-15, downstream transcription factor STAT5 have all been implicated as important regulators these processes, yet there are conflicting data regarding their contribution to vivo cell responses. We used a murine adoptive transfer model examine IL-2 IL-15 signaling...
Abstract CD8+ T cells must detect foreign antigens and differentiate into effector to eliminate infections. But, when self-antigen is recognized instead, mechanisms of peripheral tolerance prevent acquisition function avoid autoimmunity. These distinct responses are influenced by inflammatory regulatory clues from the tissue environment, but mechanism(s) which naive interpret these signals generate appropriate immune response unclear. The identification molecules operative in cell-fate...