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Principal Investigator: Filippo Veglia
Organization: WISTAR INSTITUTE
Fiscal Year: 2024
Award: $486,185
Funding agency: National Institute of Neurological Disorders and Stroke
Glioblastoma (GBM), the most aggressive and lethal form of brain cancer, is characterized by a profound
immunosuppressive microenvironment (TME) that restricts the effects of promising immunotherapies. Therefore,
there is a pressing need to develop more effective interventions to overcome this mechanism of resistance.
Tumor associated macrophages (TAMs) are a mixture of monocyte-derived macrophages (MDM) and microglia
(MG), and they are instrumental for the maintenance of the immunosuppressive state of GBM. However, there
are no effective approaches to overcome the immunosuppressive activity of TAMs in GBM, mainly due to an
incomplete understanding of TAM regulatory functions. Our long term-goal is to dissect targetable metabolic and
molecular mechanisms regulating TAM functions in the context of GBM; as these discoveries will facilitate novel
therapies to target immunosuppression and improve the dismaying outcome of GBM patients. A recent study
demonstrated that TAM are major consumers of glucose and maintain a robust glucose metabolism in the TME.
However, it has not yet been determined how GBM supports the adaptation to glucose metabolism in TAMs
and the functional consequences of this adaptation also remain elusive. Endoplasmic reticulum (ER) stress
activation is associated with the malignant progression of glioma and with the infiltration of anti-inflammatory
macrophages. PKR-like ER kinase (PERK), a critical ER stress sensor, was found to be significantly activated
in human glioma tissues, and its inhibition altered ATP/lactate production by glioma cells. Our preliminary data
expanded these findings indicating that MDM demonstrated highest glucose avidity among MG and neoplastic
cells in GBM tumors, and PERK was strongly activated in GBM infiltrating GLUT1+MDM. Contrary to MG, MDM
exhibited potent immunosuppressive activity. GLUT1+MDM were the only contributors to the suppressive activity
associated with MDM in GBM tumors. GBM-derived factors primed activation of PERK signaling in MDM, which
correlated with metabolic reprogramming resulting in high glycolysis, immunosuppressive functions, histone
lactylation, and no change in histone acetylation. Based on our crucial observations, we hypothesize that a
PERK-driven perturbation of glucose metabolism in MDM governs their immunosuppressive functions via
lactate-derived lactylation of histone lysine residues. We will test this hypothesis through the following aims:
Aim1: to elucidate underlying mechanisms of how PERK governs glycolysis in MDM in GBM tumors; Aim2:
to define glucose-driven epigenetic modifications that regulates immunosuppressive programs in MDM;
Aim3: to investigate the therapeutic potential of an epigenetic targeting approach to modulate the functions
of TAMs in GBM. The proposed studies are highly innovative because they will elucidate a previously
uncharacterized link between ER stress and glucose metabolism that regulates the activity of TAMs via
epigenetic mechanisms. Our proposal will provide a mechanistic rationale for the development of novel
therapies to target immunosuppressive TAMs and enhance the efficacy of immunotherapy in GBM patients.
Terms: <Animal Model><Animal Models and Related Studies><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Automobile Driving><Avidity><Binding><Blood monocyte><Body Tissues><Brain Cancer><CAR T cell therapy><CAR T cells><CAR T therapy><CAR modified T cells><CAR-T><CAR-Ts><CUT&RUN><Cancers><Cell Body><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cleavage Targets and Release Using Nuclease><Cleavage Under Targets and Release Using Nuclease><Clinical><Clinical Trials><Consumption><D-Glucose><Data><Development><Dextrose><ER stress><Endoplasmic Reticulum><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Ergastoplasm><Erythrocyte/Hepatoma Glucose Transporter><Exhibits><Exposure to><GLUT><GLUT1><Gene Transcription><Genes><Genetic Transcription><Glial Cell Tumors><Glial Neoplasm><Glial Tumor><Glioblastoma><Glioma><Glucose><Glucose Transporter 1><Glycolysis><Goals><Grade IV Astrocytic Neoplasm><Grade IV Astrocytic Tumor><Grade IV Astrocytoma><Histone Acetylation><Histones><Hortega cell><Human><Hypoxia><Hypoxic><Immune><Immune mediated therapy><Immunes><Immunologically Directed Therapy><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunotherapy><In Vitro><Infiltration><Intracellular Communication and Signaling><Isotopes><Kinases><L-Lysine><Label><Link><Lysine><Macrophage><Maintenance><Malignant><Malignant - descriptor><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Brain><Malignant neoplasm of brain><Maps><Marrow monocyte><Mediator><Metabolic><Microglia><Modern Man><Modification><Molecular><Molecular Interaction><Myeloid Cells><Mφ><Neuroglial Neoplasm><Neuroglial Tumor><Outcome><Oxygen Deficiency><Patients><Phosphotransferase Gene><Phosphotransferases><Play><Production><RNA Expression><Regulation><Research Specimen><Resistance><Role><SLC2A1><SLC2A1 gene><Signal Transduction><Signal Transduction Systems><Signaling><Solute Carrier Family 2, Facilitated Glucose Transporter, Member 1><Specimen><Subcellular Process><System><T cell based therapeutics><T cell based therapy><T cell directed therapies><T cell targeted therapeutics><T cell therapy><T cells for CAR><T-cell therapeutics><T-cell transfer therapy><Testing><Therapeutic><Tissues><Transcription><Transphosphorylases><Treatment Efficacy><Tumor Cell><Tumor Immunity><Tumor-associated macrophages><Work><adoptive T cell transfer><adoptive T-cell therapy><anti-tumor immunity><antitumor immunity><biological signal transduction><cancer immunity><chimeric antigen T cell receptor><chimeric antigen receptor (CAR) T cell therapy><chimeric antigen receptor (CAR) T cells><chimeric antigen receptor T cell therapy><chimeric antigen receptor T cells><chimeric antigen receptor T therapy><chimeric antigen receptor fusion protein T-cells><chimeric antigen receptor modified T cells><developmental><driving><effective intervention><endoplasmic reticulum stress><epigenetically><gene induction><gitter cell><glial-derived tumor><glioblastoma multiforme><glucose metabolism><immune microenvironment><immune suppression><immune suppressive activity><immune suppressive function><immune suppressive macrophages><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunosuppressive activity><immunosuppressive function><immunosuppressive macrophages><immunosuppressive microenvironment><immunosuppressive response><immunosuppressive tumor microenvironment><improved><in vivo><induction of genes><innovate><innovation><innovative><intervention efficacy><malignancy><mesoglia><metabolism measurement><metabolomics><metabonomics><microglial cell><microgliocyte><model of animal><monocyte><multiomics><multiple omics><neoplasm/cancer><neoplastic cell><neuroglia neoplasm><neuroglia tumor><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><new treatment approach><new treatment strategy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><panomics><perivascular glial cell><programs><promoter><promotor><resistance mechanism><resistant><resistant mechanism><sensor><social role><spongioblastoma multiforme><stressor><therapeutic T-cell platform><therapeutic efficacy><therapeutic evaluation><therapeutic testing><therapy efficacy><tumor><tumor immune microenvironment><tumor-immune system interactions>