A5042877356- Immune cells in cancer
- Immune Cell Function and Interaction
- Cancer, Hypoxia, and Metabolism
- T-cell and B-cell Immunology
- Epigenetics and DNA Methylation
- Cancer Research and Treatments
- Mast cells and histamine
- Pancreatic function and diabetes
- Adenosine and Purinergic Signaling
- PI3K/AKT/mTOR signaling in cancer
- CAR-T cell therapy research
- Long-Term Effects of COVID-19
- COVID-19 Clinical Research Studies
- Cancer Immunotherapy and Biomarkers
- Ferroptosis and cancer prognosis
- Bacterial Genetics and Biotechnology
- Protein Degradation and Inhibitors
- Cancer-related Molecular Pathways
- Genomics, phytochemicals, and oxidative stress
- Congenital heart defects research
- Cancer-related molecular mechanisms research
- Cancer-related gene regulation
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Lipid Membrane Structure and Behavior
- Pregnancy and Medication Impact
Johns Hopkins University
2014-2023
Sidney Kimmel Comprehensive Cancer Center
2014-2023
Bloomberg (United States)
2017-2023
Cancer Research Center
2014-2023
University of California, San Francisco
2022-2023
Universidad Católica de Santa Fe
2022
Johns Hopkins Medicine
2016-2021
Sidney Kimmel Cancer Center
2018-2019
University of California, Berkeley
2010
The metabolic characteristics of tumors present considerable hurdles to immune cell function and cancer immunotherapy. Using a glutamine antagonist, we metabolically dismantled the immunosuppressive microenvironment tumors. We demonstrate that blockade in tumor-bearing mice suppresses oxidative glycolytic metabolism cells, leading decreased hypoxia, acidosis, nutrient depletion. By contrast, effector T cells responded antagonism by markedly up-regulating adopting long-lived, highly activated...
Activation of mTOR-dependent pathways regulates the specification and differentiation CD4+ T effector cell subsets. Herein, we show that mTOR complex 1 (mTORC1) mTORC2 have distinct roles in generation CD8+ memory populations. Evaluation mice with a cell-specific deletion gene encoding negative regulator mTORC1, tuberous sclerosis 2 (TSC2), resulted highly glycolytic potent cells; however, due to constitutive mTORC1 activation, these cells retained terminally differentiated phenotype were...
Myeloid cells comprise a major component of the tumor microenvironment (TME) that promotes growth and immune evasion. By employing small-molecule inhibitor glutamine metabolism, not only were we able to inhibit growth, but markedly inhibited generation recruitment myeloid-derived suppressor (MDSCs). Targeting metabolism led decrease in CSF3 hence MDSCs as well immunogenic cell death, leading an increase inflammatory tumor-associated macrophages (TAMs). Alternatively, inhibiting themselves...
It is unclear why some SARS-CoV-2 patients readily resolve infection while others develop severe disease. By interrogating metabolic programs of immune cells in and recovered coronavirus disease 2019 (COVID-19) compared with other viral infections, we identify a unique population T cells. These express increased Voltage-Dependent Anion Channel 1 (VDAC1), accompanied by gene functional characteristics linked to mitochondrial dysfunction apoptosis. The percentage these increases elderly...
Abstract The mechanistic/mammalian target of rapamycin (mTOR) has emerged as a critical integrator signals from the immune microenvironment capable regulating T cell activation, differentiation, and function. precise role mTOR in control regulatory (Treg) differentiation function is complex. Pharmacologic inhibition genetic deletion promotes generation Tregs even under conditions that would normally promote effector cells. Alternatively, activity been observed to be increased Tregs, complex...
Significance Gliding is a form of enigmatic bacterial surface motility that does not use visible external structures such as flagella or pili. This study characterizes the single-molecule dynamics Myxococcus xanthus gliding motor protein AglR, homolog Escherichia coli stator MotA. However, motors, unlike stators, lack peptidoglycan-binding domains. With photoactivatable localization microscopy (PALM), we found these proteins move actively within cell membrane and generate torque by...
Myxococcus xanthus moves by gliding motility powered Type IV pili (S-motility) and a second system, A-motility, whose mechanism remains elusive despite the identification of ∼40 A-motility genes. In this study, we used biochemistry cell biology analyses to identify multi-protein complexes associated with A-motility. Previously, showed that N-terminal domain FrzCD, receptor for frizzy chemosensory pathway, interacts two proteins, AglZ AgmU. Here characterized AgmU, protein localized both...
Metabolic programming is integrally linked to immune cell function. Nowhere this clearer than in the differentiation of macrophages. Proinflammatory M1 macrophages primarily use glycolysis as a rapid energy source but also generate antimicrobial compounds, whereas alternatively activated M2 rely on oxidative phosphorylation for longevity required proper wound healing. mTOR signaling has been demonstrated be key regulator metabolism and mTORC2 generation macrophages, role mTORC1 signaling,...
T cell activation, proliferation, function, and differentiation are tightly linked to proper metabolic reprogramming regulation. By using [U-13C]glucose tracing, we reveal a critical role for GOT1 in promoting CD8+ effector function. Mechanistically, enhances proliferation by maintaining intracellular redox balance serine-mediated purine nucleotide biosynthesis. Further, promotes the glycolytic programming cytotoxic function of lymphocytes via posttranslational regulation HIF protein,...
Tissue-resident macrophages play critical roles in sentinel and homeostatic functions as well promoting inflammation immunity. It has become clear that the generation of these cells is highly dependent upon tissue-specific cues derived from microenvironment that, turn, regulate unique differentiation programs. Recently, a role for GATA6 emerged programming resident peritoneal macrophages. We identify mTOR integrating tissue regulating metabolic reprogramming. Specifically, inhibition mTORC2...
mTOR is a central integrator of metabolic and immunological stimuli, dictating immune cell activation, proliferation differentiation. In this study, we demonstrate that within clonal population activated T cells, there exist both mTORhi mTORlo cells exhibiting highly divergent immunologic functions. By taking advantage the role activation in controlling cellular size, upon antigen recognition, CD4+ are destined to become glycolytic effector cells. Conversely, preferentially develop into...
Abstract By interrogating metabolic programs in the peripheral blood mononuclear cells (PBMC) of acutely infected COVID-19 patients, we identified novel and distinct immune cell subsets Our studies a non-clonal population T expressing high H3K27me3 voltage-dependent anion channel (VDAC) with mitochondrial dysfunction increased susceptibility to death. Characterized by dysmorphic mitochondria cytoplasmic cytochrome c , apoptosis these was inhibited preventing VDAC aggregation or blocking...
Abstract The adenosine A 2A receptor (A R) is expressed in immune cells, as well brain and heart tissue, has been intensively studied a therapeutic target for multiple disease indications. Inhibitors of the R have potential stimulating response, which could be valuable cancer surveillance mounting response against pathogens. One well‐established potent selective small molecule antagonist, ZM‐241385 (ZM), short pharmacokinetic half‐life systemic toxicity due to effects heart. In this study,...
Abstract The mechanistic target of rapamycin is an essential regulator T cell metabolism and differentiation. In this study, we demonstrate that serum- glucocorticoid-regulated kinase 1 (SGK1), a downstream node complex 2 signaling, represses memory CD8+ During acute infections, murine SGK1-deficient cells adopt early precursor phenotype leading to more long-lived cells. Thus, enhanced recall capacity in response reinfection can readily reject tumors. Mechanistically, activation results...
Abstract Malignant ascites in ovarian cancer develops the setting of recurrent and advanced metastatic disease is associated with poor prognosis. Emerging evidence has demonstrated that patients have altered metabolism an immunosuppressive environment fluid. Inasmuch as rapid proliferation cells development dependent on glutamine metabolism, we hypothesized targeting can inhibit enhance anti-tumor immunity cancer. To test this hypothesis, developed a novel small molecule antagonist (prodrug...
Abstract Adenosine signaling through the A2a receptor (A2aR) has pleiotropic immunosuppressive effects on a broad range of immune cells. Extracellular adenosine levels, which are typically very low in normal tissues, elevated tumor microenvironment, allowing increased A2aR. Previously, our lab and others have shown rejection tumors A2aR-null mice, demonstrating that A2aR limits immunologic response to tumors. Present work demonstrates ability potent specific, orally administered antagonist,...
Abstract In order to study mechanistic/mammalian target of rapamycin’s role in T cell differentiation, we generated mice which Rheb is selectively deleted cells (T-Rheb−/− C57BL/6J background). During these studies, noted that T-Rheb−/− were consistently heavier but had improved glucose tolerance and insulin sensitivity as well a marked increase beige fat. Microarray analysis Rheb−/− revealed expression kallikrein 1–related peptidase b22 (Klk1b22). Overexpression KLK1b22 vitro enhanced...