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Principal Investigator: Greg M. Delgoffe
Organization: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
Fiscal Year: 2024
Award: $640,384
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY/ABSTRACT
The successes of immunotherapies like blockade of co-inhibitory `checkpoint' molecules have changed the
treatment paradigm of cancer. However, the fact that robust responses are restricted to a subset of patients
highlights the need to further understand the biology of exhausted T cells: what drives their differentiation,
maintains their dysfunction, and how they may be reinvigorated to eradicate tumor cells. Our lab and others
have revealed that metabolic stress and mitochondrial dysfunction are key drivers in T cell exhaustion, both
from a cell extrinsic and cell intrinsic perspective. We recently reported that mitochondrial stress and reactive
oxygen species (ROS) production, driven to intolerable levels under hypoxic environments in the face of
persistent antigen, was sufficient to deviate cells into a terminally exhausted fate. Antioxidants both
pharmacologic and genetic could bias T cell differentiation away from exhaustion to more functional fates. But precisely how ROS production alters T cell fate and function remains unclear. One of the more intriguing
observations was elevating ROS via mitochondrial dysfunction altered T cell signaling: as peroxide is one of
the more potent inhibitors of tyrosine phosphatases, elevating ROS alone mimicked TCR and other
phosphotyrosine signals. ROS also dramatically reprograms cellular metabolism: by inhibiting aconitase, citrate is driven from the mitochondria where it is converted to acetyl-CoA, acting as a substrate for de novo
lipogenesis. As a result, while exhausted cells possess dysfunctional mitochondria and compete poorly for
glucose, they are loaded with lipid droplets and repress fatty acid oxidiation and lipolysis. While we know that
mitochondrial stress can drive T cells to exhaustion and that terminally exhausted T cells are metabolically
insufficient, the mechanisms that ultimately drive and enforce the phenotype remain unclear. In this Proposal,
we will identify the metabolic underpinnings of T cell exhaustion: how metabolic stress can interfere with
signaling, transcription, and differentiation. AIM 1: Determine how oxidative stress alters T cell signaling
cascades at the level of phosphatase inhibition. ROS play central roles in signaling as inhibitors of tyrosine
phosphatases. We will determine the role of ROS in exhausted T cell function in vivo, and use proteomics and
transcriptomic technologies to identify the phosphorylation cascades susceptible to ROS induction. AIM 2:
Identify how ROS-mediated changes in metabolic flux undermine T cell function. In this Aim, we will explore
the role increased lipid storage plays in T cell function and ask whether these elevated levels of lipids
represent `dead weight' or an untapped fuel source. AIM 3: Define the importance of altered nutrient pathways induced through oxidative stress responses. Our data suggest Slc16a11 similarly supports lactate uptake into exhausted T cells and maintains their dysfunctional state. Using a conditional knockout mouse and blocking antibodies, we will determine the importance of monocarboxylate metabolism in exhausted T cell biology.
Terms: <Acetyl CoA><Acetyl Coenzyme A><Acetylcysteine><Acetylin><Aconitase><Aconitate Hydratase><Active Oxygen><Airbron><Antigens><Antioxidants><Atrophic><Atrophy><Biology><Blocking Antibodies><Body Tissues><Broncholysin><Brunac><Cancers><Cell Body><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cellular biology><Characteristics><Chronic><Citrate Hydrolyase><Citrate(isocitrate) hydro-lyase><Citrates><Citric Acid Cycle><Clinical Treatment Moab><Cytosol><Cytosolic Protein Tyrosine Phosphastase><D-Glucose><Data><Dextrose><Dysfunction><Environment><Exposure to><Fabrol><Fatty Acids><Fluatox><Fluimucetin><Fluimucil><Fluprowit><Functional disorder><Gene Transcription><Genes><Genetic><Genetic Transcription><Glucose><Hypoxia><Hypoxic><Immune><Immune infiltrates><Immune mediated therapy><Immunes><Immunity><Immunologically Directed Therapy><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunotherapy><In Vitro><Intermediary Metabolism><Intracellular Communication and Signaling><Isocitrate Hydro-Lyase><KO mice><Knock-out Mice><Knockout Mice><Krebs Cycle><Lipids><Lipolysis><Lytotoxicity><Malignant Neoplasms><Malignant Tumor><Mediating><Mercapturic Acid><Metabolic><Metabolic Processes><Metabolic stress><Metabolism><Mitochondria><Modality><Modeling><Monoclonal Antibodies><Muco Sanigen><Mucocedyl><Mucolator><Mucolyticum><Mucomyst><Mucosolvin><Mucret><N-Acetylcysteine><NAC Zambon><Neo-Fluimucil><Null Mouse><Nutrient><O element><O2 element><Obesity><Oxidative Stress><Oxygen><Oxygen Deficiency><Oxygen Radicals><PD 1><PD-1><PD-1 blockade><PD1><PD1 blockade><PTP Family Gene><PTPase><Parvolex><Pathway interactions><Patients><Peroxides><Phenotype><Phosphatases><Phosphohydrolases><Phosphomonoesterases><Phosphoric Monoester Hydrolases><Phosphorylation><Phosphotyrosine><Phosphotyrosine Phosphatase><Phosphotyrosyl Protein Phosphatase><Physiopathology><Play><Predisposition><Pro-Oxidants><Production><Protein Phosphorylation><Protein Tyrosine Phosphatase><Protein Tyrosine Phosphatase Gene><Proteome><Proteomics><RNA Expression><Reactive Oxygen Species><Receptor Type PTP Gene><Regulatory T-Lymphocyte><Reporting><Repression><Respaire><Role><S-acetate Coenzyme A><Signal Transduction><Signal Transduction Systems><Signaling><Source><Stress><Subcellular Process><Susceptibility><T cell differentiation><T-Cells><T-Lymphocyte><TCA cycle><Technology><Tissues><Tixair><Transcription><Treg><Tricarboxylic Acid Cycle><Tumor Cell><Tumor Immunity><Tyrosine Phosphatase><Tyrosine-O-phosphate><Tyrosyl Phosphoprotein Phosphatase><Up-Regulation><Upregulation><Weight><adipogenesis><adiposity><anti-PD-1 blockade><anti-PD1 blockade><anti-cancer><anti-tumor immune response><anti-tumor immunity><antitumor immunity><biological adaptation to stress><biological signal transduction><cancer immunity><cell biology><conditional knock-out><conditional knockout><corpulence><cytokine><cytotoxic><cytotoxicity><design><designing><exhaust><exhaustion><fatty acid oxidation><glucose uptake><immune cell infiltrate><immune suppression><immune suppressive activity><immune suppressive function><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunogen><immunosuppressive activity><immunosuppressive function><immunosuppressive response><improved><in vivo><inhibitor><lipid biosynthesis><lipogenesis><mAbs><malignancy><member><mitochondrial><mitochondrial dysfunction><monoclonal Abs><neoplasm/cancer><neoplastic cell><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><nutrient deprivation><nutritional deprivation><overexpress><overexpression><pathophysiology><pathway><patient subclass><patient subcluster><patient subgroups><patient subpopulations><patient subsets><patient subtypes><pharmacologic><prevent><preventing><progenitor><programmed cell death 1><programmed cell death protein 1><programmed death 1><programs><protein tyrosine phosphate phosphohydrolase><reaction; crisis><regulatory T-cells><response><self-renew><self-renewal><sle2><social role><stress response><stress; reaction><success><systemic lupus erythematosus susceptibility 2><thymus derived lymphocyte><transcriptomics><tumor eradication><tumor growth><uptake><weights>