A5048962876- Immune Cell Function and Interaction
- CAR-T cell therapy research
- Cancer Immunotherapy and Biomarkers
- Immune cells in cancer
- Prostate Cancer Treatment and Research
- Immunotherapy and Immune Responses
- T-cell and B-cell Immunology
- Cancer, Hypoxia, and Metabolism
- Diet and metabolism studies
- Genetics, Aging, and Longevity in Model Organisms
- Virus-based gene therapy research
- Cancer, Lipids, and Metabolism
- Diabetes and associated disorders
- Viral Infectious Diseases and Gene Expression in Insects
- RNA modifications and cancer
- Adipose Tissue and Metabolism
- Ubiquitin and proteasome pathways
- Peroxisome Proliferator-Activated Receptors
- HIV Research and Treatment
- Tryptophan and brain disorders
- Pluripotent Stem Cells Research
- Epigenetics and DNA Methylation
- RNA Research and Splicing
- Adenosine and Purinergic Signaling
- CRISPR and Genetic Engineering
Vanderbilt University Medical Center
2025
Van Andel Institute
2016-2024
UPMC Hillman Cancer Center
2018-2023
University of Pittsburgh
2018-2022
Hope College
2015
Despite remarkable responses to cancer immunotherapy in a subset of patients, many patients remain resistant these therapies. The tumor microenvironment can impose metabolic restrictions on T cell function, creating resistance mechanism immunotherapy. We have previously shown tumor-infiltrating cells succumb progressive loss sufficiency, characterized by repression mitochondrial activity that cannot be rescued PD-1 blockade. 4-1BB, costimulatory molecule highly expressed exhausted cells, has...
How environmental nutrient availability impacts T cell metabolism and function remains poorly understood. Here, we report that the presence of physiologic carbon sources (PCSs) in culture medium broadly glucose utilization by CD8+ cells, independent transcriptional changes metabolic reprogramming. The PCSs reduced contribution to TCA cycle increased effector with lactate directly fueling cycle. In fact, cells responding Listeria infection preferentially consumed over as a substrate vitro,...
Environmental nutrient availability influences T cell metabolism, impacting function and shaping immune outcomes. Here, we identified ketone bodies (KBs)-including β-hydroxybutyrate (βOHB) acetoacetate (AcAc)-as essential fuels supporting CD8
Cellular immunotherapies for cancer represent a means by which patient's immune system can be augmented with high numbers of tumor-specific T cells. Chimeric antigen receptor (CAR) therapy involves genetic engineering to 'redirect' peripheral cells tumor targets, showing remarkable potency in blood cancers. However, due several resistance mechanisms, CAR-T cell therapies remain ineffective solid tumors. We and others have shown the microenvironment harbors distinct metabolic landscape that...
Coordination of cellular metabolism is essential for optimal T cell responses. Here, we identify cytosolic acetyl-CoA production as an metabolic node CD8 function in vivo. We show that responses to infection depend on derived from citrate via the enzyme ATP lyase (ACLY). However, ablation ACLY triggers alternative, acetate-dependent pathway mediated by acyl-CoA synthetase short-chain family member 2 (ACSS2). Mechanistically, acetate fuels both TCA cycle and production, impacting effector...
While checkpoint blockade immunotherapies have widespread success, they rely on a responsive immune infiltrate; as such, treatments enhancing infiltration and preventing immunosuppression are of critical need. We previously generated αPD-1 resistant variants the murine HNSCC model MEER. entirely resistant, these tumors regress after single dose oncolytic vaccinia virus (VV). then VV-resistant MEER line to dissect immunologic features sensitive tumors. treatment both tumor types induced IFNγ,...
Abstract Imbalanced effector and regulatory CD4+ T cell subsets drive many inflammatory diseases. These rely on distinct metabolic programs, modulation of which differentially affects fate function. Lipid metabolism is fundamental yet remains poorly understood across subsets. Therefore, we performed targeted in vivo CRISPR/Cas9 screens to identify lipid genes pathways essential for functions. established mitochondrial fatty acid synthesis Mecr, Mcat, Oxsm as key regulators. Of these, the...
Abstract Asymmetric cell division is critical during development, as it influences processes such fate specification and migration. We have characterized FRK-1, a homolog of the mammalian Fer nonreceptor tyrosine kinase, found to be required for differentiation maintenance epithelial types, including stem cell-like seam cells hypodermis. A genomic knockout frk-1, allele ok760, results in severely uncoordinated larvae that arrest at L1 stage an excess number lateral hypodermal appear lost...
Reducing calorie intake without malnutrition limits tumor progression but the underlying mechanisms are poorly understood. Here we show that dietary restriction (DR) suppresses growth by enhancing CD8
Abstract Environmental nutrient availability influences T cell metabolism, impacting function and shaping immune outcomes. However, the metabolic pathways critical for optimal responses remain poorly understood. Here, we identify ketone bodies (KBs) – including β-hydroxybutyrate (βOHB) acetoacetate (AcAc) as essential fuels supporting CD8 + metabolism effector function. Ketolysis is an intrinsic feature of highly functional (Teff) cells βOHB directly increases Teff IFN-γ production cytolytic...
<h3>Background</h3> Blockade of co-inhibitory 'checkpoint' molecules, PD-1 and CTLA-4, has induced impressive clinical responses in advanced tumors; yet only a subset patients.<sup>1–3</sup> Limited success with checkpoint blockade therapy suggests other cell extrinsic or intrinsic mechanisms may be dampening an effective immune response. Cytotoxic CD8+ T cells (CTL) encountering chronic antigen metabolic restriction can differentiate to terminally exhausted state (Texh), marked by...
<h3>Background</h3> While CD8+ cytotoxic T cells are clearly critical for identification and elimination of cancer cells, factors concentrated within the tumor microenvironment drive altered differentiation these to a hypofunctional, short-lived state termed cell exhaustion<sup>1</sup> (figure 1a). Exhaustion is progressive lineage, it now clear that terminally exhausted (tTexh) not targets checkpoint blockade immunotherapy but may serve as limit immunotherapeutic efficacy.<sup>2–6</sup>...
Abstract While CD8+ cytotoxic T cells are clearly critical for identification and elimination of cancer cells, factors concentrated within the tumor microenvironment drive their altered differentiation to a hypofunctional, short-lived state termed exhaustion. Exhaustion is progressive lineage, it now clear that most terminally exhausted (tTexh) not targets checkpoint blockade immunotherapy but rather serve as limit immunotherapeutic efficacy. Compared directly, tumor-infiltrating tTexh bear...
Abstract Overexpression of Myc and loss Pten are very common oncogenic events in prostate cancer. However, why these specific events, as opposed to others, involved cancer develop remains unclear. While the impact on cell proliferation is well-characterized, their role differentiation resulting tumorigenesis poorly understood. We recently developed an vitro model which basal epithelial cells (PrECs) can be differentiated into secretory luminal cells. Our offers several advantages, that it...
Abstract Many genes aberrantly expressed in prostate cancer are involved normal basal to luminal cell differentiation. We previously demonstrated that transient ING4 expression is required for differentiation and downregulated ~60% of primary tumors. further a model overexpressing ERG, MYC, shPTEN (EMP) loss PTEN was responsible loss. Furthermore, half the human tumor samples lose have also lost PTEN. However, we did not know how inhibits expression. Utilizing our vitro model, whereby...
<h3>Background</h3> Durable clinical responses to immune checkpoint blockade (ICB) occur in a limited fraction of patients. We thus hypothesized that the characteristic tumor metabolic switch towards aerobic glycolysis could contribute ICB resistance. High glucose consumption and lactate production by cells can indeed restrict nutrient availability for tumor-infiltrating T cells, which also rely on proliferate function. Therefore, we investigated whether targeting metabolism potentiates...
<h3>Background</h3> Regulatory T (Treg) cells are vital for preventing autoimmunity but a major barrier to robust cancer immunity as the tumor microenvironment (TME) recruits and promotes their function. The deregulated cellular metabolism of leads metabolite-depleted, hypoxic, acidic TME. While TME impairs effector function highly glycolytic infiltrating CD8 cells, Treg cell suppressive is maintained. Further, studies in vitro induced ex vivo reveal distinct metabolic profile compared...
<h3>Background</h3> Oncolytic viruses are an underappreciated immunotherapy capable of inflaming the tumor microenvironment (TME), vaccinating a patient against their own tumor, and delivering gene therapy to TME. However, apart from oncolytic HSV T-vec, these therapies have not seen widespread use, due in part incomplete understanding immunologic mechanisms action. We sought determine features vaccinia virus (VV) response resistance using subclones HPV+ head neck cancer model MEER rendered...