A5091728889- Immune Cell Function and Interaction
- CAR-T cell therapy research
- Cancer Immunotherapy and Biomarkers
- Endoplasmic Reticulum Stress and Disease
- Colorectal Cancer Surgical Treatments
- Cancer Research and Treatments
- Autophagy in Disease and Therapy
- Colorectal and Anal Carcinomas
- Immunotherapy and Immune Responses
- Cancer, Hypoxia, and Metabolism
- Immune cells in cancer
- T-cell and B-cell Immunology
- Genomics, phytochemicals, and oxidative stress
- Diabetes and associated disorders
- Reproductive System and Pregnancy
- RNA modifications and cancer
- Preterm Birth and Chorioamnionitis
- Immune Response and Inflammation
- Tryptophan and brain disorders
- Phagocytosis and Immune Regulation
- CRISPR and Genetic Engineering
- PARP inhibition in cancer therapy
- Pancreatic function and diabetes
- Synthesis and Biological Evaluation
- Synthesis and pharmacology of benzodiazepine derivatives
University of North Carolina at Chapel Hill
2022-2024
UNC Lineberger Comprehensive Cancer Center
2022-2024
Communities In Schools of Orange County
2022-2023
Harvard University
2023
Center for Systems Biology
2023
MUSC Hollings Cancer Center
2014-2021
Medical University of South Carolina
2013-2021
University of Charleston
2021
United States Army Medical Research and Development Command
2015
College of Charleston
2014
The solid tumor microenvironment (TME) imprints a compromised metabolic state in tumor-infiltrating T cells (TILs), hallmarked by the inability to maintain effective energy synthesis for antitumor function and survival. TME must catabolize lipids via mitochondrial fatty acid oxidation (FAO) supply nutrient stress, it is established that enriched FAO are adept at cancer control. However, endogenous TILs unmodified cellular therapy products fail sustain bioenergetics tumors. We reveal imposes...
Pregnancy outcome is severely compromised by intrauterine infections and inflammation. Although the pregnant uterine microenvironment replete with innate immune cells TLR expression, mechanisms that facilitate adverse effects of their activation are largely unknown. In this study, we mimic TLR9 its pathogenic ligand hypomethylated CpG demonstrate IL-10 proficiency protects against CpG-induced pregnancy complications. We show fetal resorption preterm birth rapidly induced in IL-10(-/-) mice...
Abstract Tumor antigen–specific T cells rapidly lose energy and effector function in tumors. The cellular mechanisms by which loss inhibition of occur tumor-infiltrating lymphocytes (TILs) are ill-defined, methods to identify tumor TILs that experience such stress unknown. Processes upstream the mitochondria guide cell-intrinsic depletion. We hypothesized a mechanism T-cell–intrinsic consumption was process oxidative protein folding disulfide bond formation takes place endoplasmic reticulum...
The cytokine B cell activation factor of the TNF family (BAFF) is considered to perform a proinflammatory function. This paradigm particularly true for cell-dependent immune responses; however exact role BAFF in regulating T immunity ill-defined. To directly assess effect upon cells, we analyzed responses BAFF-transgenic (Tg) mice. We found that BAFF-Tg mice are profoundly compromised, as indicated by their acceptance islet allografts and delayed skin graft rejection. However, purified...
Molecular chaperones control a multitude of cellular functions via folding chaperone-specific client proteins. CD4+FOXP3+ Tregs play key roles in maintaining peripheral tolerance, which is subject to regulation by multiple molecular switches, including mTOR and hypoxia-inducible factor. It not clear whether GP96 (also known as GRP94), master TLR integrin chaperone, controls Treg function. Using murine genetic models, we demonstrated that required for maintenance function, loss resulted...
Abstract Adoptive T cell transfer therapy induces objective responses in patients with advanced malignancies. Despite these results, some individuals do not respond due to the generation of terminally differentiated cells during expansion protocol. As gamma and delta catalytic subunits PI3K pathway are abundant leukocytes involved activation, we posited that blocking both ex vivo inhibitor IPI‐145 would prevent their differentiation, thereby increasing antitumor activity vivo. However,...
Abstract Generating stem-like memory T cells (TSCM) is a potential strategy to improve adoptive immunotherapy. Elucidating optimal ways modulate signaling pathways that enrich TSCM properties could identify approaches achieve this goal. We discovered herein blocking the PI3Kδ pathway pharmaceutically varying degrees can generate with increasingly heightened stemness properties, based on progressive enrichment of transcription factors Tcf1 and Lef1. enhanced features exhibited metabolic...
Infection and inflammation can disturb immune tolerance at the maternal-fetal interface, resulting in adverse pregnancy outcomes. However, underlying mechanisms for detrimental responses remain ill defined. In this study, we provide evidence programming of fetal loss response to polyinosinic:polycytidylic acid (polyI:C), a viral mimic an inducer inflammatory milieu. IL-10 uterine NK (uNK) cells expressing activating receptor NKG2D play critical role poly(I:C)-induced demise. wild type (WT)...
The endoplasmic reticulum (ER) is an energy-sensing organelle with intimate ties to programming cell activation and metabolic fate. T-cell receptor (TCR) represents a form of acute stress induces mobilization ER Ca2+ stores. role the in fate remains largely undefined. Gp96 protein functions as molecular chaperone buffering protein. We hypothesized that response may be important for CD4+ gp96 integral this process. To test our hypothesis, we utilized genetic deletion gene Hsp90b1 T...
Abstract Protein synthesis supports robust immune responses. Nutrient competition and global cell stressors in the tumor microenvironment (TME) may impact protein translation T cells antitumor immunity. Using human mouse tumors, we demonstrated here that is repressed solid tumors. Reduced glucose availability to TME led activation of unfolded response (UPR) element eIF2α (eukaryotic initiation factor 2 alpha). Genetic models revealed attenuation mediated by activated p-eIF2α undermines...
Abstract The requisites for protein translation in T cells are poorly understood and how shapes the antitumor efficacy of is unknown. Here we demonstrated that IL15-conditioned were primed by metabolic energy sensor AMP-activated kinase to undergo diminished relative effector cells. However, showed exhibited a remarkable capacity enhance their tumors, which unable duplicate. Studying modulation applications cancer immunotherapy revealed direct ex vivo pharmacologic inhibition elongation...
Effective cancer therapies simultaneously restrict tumor cell growth and improve anti-tumor immune responses. Targeting redox-dependent protein folding enzymes within the endoplasmic reticulum (ER) is an alternative approach to activation of unfolded response (UPR) a novel therapeutic platform induce malignant death. E64FC26 recently identified disulfide isomerase (PDI) inhibitor that activates UPR, oxidative stress, apoptosis in cells, but not normal types. Given targeting cellular redox...
Physiological stress responses have been suggested as a mechanism through which social and biological factors contribute to racial disparities in breast cancer outcomes. Many African Americans experience stressful life events circumstances. These may an increased risk of advanced stage disease at diagnosis and/or faster progression, but not all American women exposed adverse develop disease. Similarly, who limited number stressors can cancer. Highly individualized reactivity account for...
Background Adoptive T cell transfer (ACT) therapy improves outcomes in patients with advanced malignancies, yet many individuals relapse due to the infusion of cells poor function or persistence. Toll-like receptor (TLR) agonists can invigorate antitumor responses when administered directly patients, but these often coincide toxicities. We posited that TLR could be repurposed ex vivo condition remarkable potency vivo, circumventing TLR-related toxicity. Methods In this study we investigated...
Transcription factors (TFs) regulate the differentiation of T cells into diverse states with distinct functionalities. To precisely program desired cell in viral infections and cancers, we generated a comprehensive transcriptional epigenetic atlas nine CD8 + for TF activity prediction. Our analysis catalogued fingerprints each state, uncovering new regulatory mechanisms that govern selective state differentiation. Leveraging this platform, focused on two critical tumor virus control:...
CD24 binds to and suppresses inflammation triggered by danger-associated molecular patterns such as heat shock proteins (HSPs) high-mobility group box 1. Paradoxically, has been shown enhance autoimmune disease. In this study, we attempt reconcile paradox deletion of (24KO) in a lupus-like disease model driven forced expression HSP gp96 at the cell surface (transgenic mice [tm]). As expected, tm24KO showed increased CD11c(+) dendritic activation coupled significant increase cell-specific...