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Understanding Metabolic and Epigenetic Cross‐ talk in Potent Anti‐ tumor T cells

了解强效抗肿瘤 T 细胞中的代谢和表观遗传交叉对话

基本信息

批准号：
10163144
负责人：
Shikhar Mehrotra
金额：
$ 46.37万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-12 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10163144
关键词：
Acetylation Adoptive Cell Transfers Adoptive Transfer Aging Antibodies Antigens Antitumor Response Autologous Biological Process CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Calcium Cell Death Cells Chromatin Clinical Data Deacetylation Dependence Energy Metabolism Epigenetic Process Epitopes Equilibrium Event Exhibits FOXP3 gene Failure Functional disorder Glutamine Helper-Inducer T-Lymphocyte Histone Deacetylase Homeostasis Human Human Engineering Hybrids Hydrolase IL2 gene Immune system Immunotherapy Interferon Type II Interleukin-17 Investigation Lead Malignant Neoplasms Mediating Memory Metabolic Metabolism Methylation Modality Modification Molecular Mus Natural Killer Cells Nicotinamide adenine dinucleotide PD-1 blockade PPBP gene Patients Phenotype Post-Translational Protein Processing Primary Neoplasm Property Proteins Protocols documentation Publishing Regulation Regulatory T-Lymphocyte Reporter Reporting Role SIRT1 gene Sirtuins Solid Neoplasm T cell response T cell therapy T memory cell T-Lymphocyte T-Lymphocyte Subsets TC1 Cell TNF gene Testing Th1 Cells Transferase Translating Tumor-Infiltrating Lymphocytes Work Xenograft Model anti-PD1 antibodies base cancer therapy clinical practice cofactor combinatorial cytokine engineered T cells epigenome exhaustion genetic signature improved improved outcome in vivo infectious disease model metabolic profile mitochondrial metabolism mouse model neoplasm immunotherapy novel pre-clinical preclinical study preservation programmed cell death protein 1 programs receptor response stem cell fate stem-like cell stemness transcriptome sequencing tumor tumor growth tumor microenvironment

项目摘要

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.

摘要