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Principal Investigator: Shikhar Mehrotra
Organization: MEDICAL UNIVERSITY OF SOUTH CAROLINA
Fiscal Year: 2024
Award: $440,560
Funding agency: National Cancer Institute
ABSTRACT
Recent preclinical studies have shown that different subsets of both helper CD4+ T helper (Th) cells and CD8+
T cytotoxic (Tc) cells hold promise for clinical use in adoptive cell therapy (ACT) protocols. Importantly, T
helper cell subsets with the ability to secrete IL-17 (Th17) have been shown to possess stem cell like
phenotype that attributes to their long-term persistence and leads to improved tumor control tumors as
compared to the Th1 subsets (that secrete IFNγ, IL2, TNFα). However, contrary to these observations there
are reports that Tc1 cells exhibit improved tumor control as compared to Tc17 cells. These differences in T cell
subsets response to control tumors is compounded by the fact that in the suppressive tumor microenvironment
a large fraction of tumor reactive T cells acquire FoxP3+ regulatory phenotype, become dysfunctional or
undergo cell death leading to tumor reversion. Thus, ex vivo programming conditions that can render T cells a
stable phenotype, which not only controls primary tumors but also results in the formation of anti-tumor
memory will be of immense importance for ACT. We have recently established that programming conditions
that bring together ‘anti-tumor effector function’ of Th1 cells and ‘stemness’ of Th17 cells lead to a superior
hybrid Th1/17 cells exhibiting long-term tumor control. Importantly, these ex vivo programming conditions also
generate highly effective hybrid Tc1/Tc17 cells and render human tumor infiltrating lymphocytes (TILs) with
increased cytokine secreting ability. Importantly, the hybrid T cells exhibited higher levels of nicotinamide
adenine dinucleotide (NAD+), a cofactor that serves as substrate for Sirtuins and regulates multiple metabolic
and epigenetic molecules. We hypothesize that the robust long-term tumor control was observed with hybrid
Th1/17 cells was mediated by an overall rejuvenated T cell phenotype due to high NAD+ that influenced a
combination of events including post-translational modifications, and epigenetic stability that led to
metabolically fit phenotype. Given the crucial role of NAD+ in a variety of biological processes including energy
metabolism, aging, calcium homeostasis, and epigenome, we propose the following aims to test the above
hypothesis: Aim 1) To determine if metabolic signature and anti-tumor phenotype of the cytokine subsets in
hybrid T1/17 cells could be translated to program tumor infiltrating lymphocytes; Aim 2) To determine if
antibody mediated combinatorial inhibition of CD38 with PD1 antibody leads to robust anti-tumor response in
different preclinical in vivo and xenograft models; and Aim 3) To determine how NAD+ level contributes to
metabolo-epigenetic programming that preserves robust anti-tumor response in T1/17 hybrid and CD38-KO T
cells. We believe that this proposal to determine the central mechanism that results in superior anti-tumor
response by hybrid T1/17 cells will be important to adapt these ex vivo programming conditions for immediate
translational use in adoptive T-cell immunotherapy.
Terms: <(TNF)-α><Acetylation><Adoptive Cell Transfers><Adoptive Transfer><Aging><Aldesleukin Gene><Antibodies><Antigenic Determinants><Antigens><Antitumor Response><Autologous><Autoregulation><Beta-TG><Binding Determinants><Biological Function><Biological Process><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CTAP III><CTAP3><CTAPIII><CTLA-8><CTLA-8 Gene><CTLA8><CTLA8 Gene><CXC Chemokine Ligand 7><CXCL7><Cachectin><Calcium><Cancer Treatment><Cancers><Cell Body><Cell Death><Cell-Mediated Lympholytic Cells><Cells><Chromatin><Clinical><Connective Tissue-Activating Peptide III><Cytolytic T-Cell><Cytotoxic T Cell><Cytotoxic T-Lymphocyte-Associated Antigen 8><Cytotoxic T-Lymphocyte-Associated Antigen 8 Gene><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8 Gene><Cytotoxic T-Lymphocytes><Data><Deacetylation><Dependence><Dihydronicotinamide Adenine Dinucleotide><Diphosphopyridine Nucleotide><Dysfunction><Energy Expenditure><Energy Metabolism><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epitopes><Equilibrium><Event><Exhibits><FOXP3><FOXP3 gene><Failure><Forkhead Box P3><Functional disorder><Gln><Glutamine><HDAC><HDAC Proteins><Helper Cells><Helper T-Cells><Helper T-Lymphocytes><Helper-Inducer T-Cells><Helper-Inducer T-Lymphocyte><Histone Deacetylase><Homeostasis><Human><Human Engineering><Hybrids><Hydrolase><Hydrolase Family Gene><Hydrolase Gene><IFN-Gamma><IFN-g><IFN-γ><IFNG><IFNγ><IL-17><IL-17 Gene><IL-17A><IL-17A Gene><IL-2 Gene><IL17><IL17 Protein><IL17 gene><IL17A><IL17A Gene><IL2><IL2 gene><Immune Interferon><Immune mediated therapy><Immune system><Immunologically Directed Therapy><Immunotherapy><Inducer Cells><Inducer T-Lymphocytes><Interferon Gamma><Interferon Type II><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8)><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8) Gene><Interleukin 17 Precursor><Interleukin 17 Precursor Gene><Interleukin 2 Precursor Gene><Interleukin-17><Interleukin-2 Gene><Intermediary Metabolism><Investigation><JM2><L-Glutamine><LA-PF4><Lead><Learning><Macrophage-Derived TNF><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Mediating><Memory><Metabolic><Metabolic Processes><Metabolism><Methylation><Mice><Mice Mammals><Modality><Modern Man><Modification><Molecular><Monocyte-Derived TNF><Murine><Mus><NAP-2><NAP2><Nadide><Neutrophil-Activating Peptide 2><Nicotinamide adenine dinucleotide><Nicotinamide-Adenine Dinucleotide><PBP gene><PBP protein><PD 1><PD-1><PD-1 antibody><PD-1 blockade><PD1><PD1 antibody><PD1 blockade><PPBP><PPBP gene><Patients><Pb element><Phenotype><Physiological Homeostasis><Physiopathology><Platelet Basic Protein><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modifications><Posttranslational Protein Processing><Primary Neoplasm><Primary Tumor><Pro-Platelet Basic Protein><Property><Protein Modification><Proteins><Protocol><Protocols documentation><Publishing><Q Levoglutamide><Q. Levoglutamide><RNA Seq><RNA sequencing><RNAseq><Receptor Protein><Regulation><Regulatory T-Lymphocyte><Rejuvenation><Reporter><Reporting><Role><SCURFIN><SCYB7><SIRT1><SIRT1 gene><Silent Mating Type Information Regulator 2-like Proteins><Sir2-like Proteins><Sirtuin 1><Sirtuins><Small Inducible Cytokine Subfamily B, Member 7><Solid Neoplasm><Solid Tumor><Stem Cell like><T cell based therapeutics><T cell based therapy><T cell directed therapies><T cell response><T cell targeted therapeutics><T cell therapy><T memory cell><T-Cell Growth Factor Gene><T-Cell Subsets><T-Cells><T-Lymphocyte><T-Lymphocyte Subsets><T-cell therapeutics><T-cell transfer therapy><T4 Cells><T4 Lymphocytes><T8 Cells><T8 Lymphocytes><TC1><TC1 Cell><TC2><TCGF Gene><TGB1><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Testing><Th-1 Cell><Th1 Cells><Thrombocidin 1><Thrombocidin 2><Thromboglobulin, Beta-1><Transferase><Transferase Gene><Translating><Treg><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Tumor-Infiltrating Lymphocytes><Type 1 Helper Cell><Work><Xenograft Model><adoptive T cell transfer><adoptive T-cell therapy><adoptive cell therapy><adoptive cellular therapy><anti-PD-1 Ab><anti-PD-1 antibodies><anti-PD-1 blockade><anti-PD-1 monoclonal antibodies><anti-PD1 Ab><anti-PD1 antibodies><anti-PD1 blockade><anti-PD1 monoclonal antibodies><anti-cancer therapy><anti-programmed cell death protein 1 antibodies><anti-programmed death-1 antibody><anti-tumor immune therapy><anti-tumor immunotherapy><anti-tumor response><balance><balance function><beta-Thromboglobulin><cancer infiltrating T cells><cancer microenvironment><cancer therapy><cancer-directed therapy><clinical practice><cofactor><combinatorial><cytokine><cytotoxic CD8 T cells><cytotoxic CD8 T lymphocyte><ecto-nucleotidase><engineered T cells><epigenetically><epigenome><exhaustion><gene signatures><genetic signature><genetically engineered T-cells><heavy metal Pb><heavy metal lead><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunogen><improved><improved outcome><in vivo><infectious disease model><killer T cell><lFN-Gamma><malignancy><memory T lymphocyte><metabolic profile><mitochondrial metabolism><mouse model><murine model><necrocytosis><neoplasm immunotherapy><neoplasm/cancer><novel><pathophysiology><pre-clinical><pre-clinical study><preclinical><preclinical study><preservation><progenitor cell fate><progenitor fate><programmed cell death 1><programmed cell death protein 1><programmed death 1><programs><receptor><regulatory T-cells><response><sle2><social role><stem and progenitor cell fate><stem cell characteristics><stem cell fate><stemness><systemic lupus erythematosus susceptibility 2><therapeutic T-cell platform><thymus derived lymphocyte><transcriptome sequencing><transcriptomic sequencing><transgenic T- cells><tumor><tumor growth><tumor immune therapy><tumor immunotherapy><tumor infiltrating T cells><tumor microenvironment><xenograft transplant model><xenotransplant model><β-TG><β-Thromboglobulin>