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.

抽象的最近的临床前研究表明，辅助CD4+ T Helper（Th）细胞和CD8+的不同子集不同 T细胞毒性（TC）细胞有望在适应性细胞疗法（ACT）方案中使用临床使用。重要的是，t 具有分泌IL-17（TH17）能力的辅助细胞子集已证明具有干细胞将其长期持久性归因于表型，并导致肿瘤对照肿瘤的改善与TH1亚集（那个秘密的IFNγ，IL2，TNFα）相比。但是，与那里的这些观察结果对比有报道称，与TC17细胞相比，TC1细胞暴露了改善的肿瘤控制。 T细胞中的这些差异子集对对照肿瘤的反应是由抑制性肿瘤微环境中的事实更加复杂的。大部分肿瘤反应性T细胞获得FOXP3+调节表型，变得功能失调或经历细胞死亡，导致肿瘤逆转。那是可以使T细胞a的体内编程条件稳定的表型，不仅控制原发性肿瘤，而且还会导致抗肿瘤的形成记忆对于行为至关重要。我们最近确定了编程条件这汇集了Th1细胞的“抗肿瘤效应函数”和Th17细胞的“茎”导致了上等杂交TH1/17细胞激发了长期肿瘤对照。重要的是，这些离体编程条件也生成高效的杂化TC1/TC17细胞，并与人类肿瘤浸润淋巴细胞（TIL）增加细胞因子分泌能力。重要的是，混合T细胞暴露了较高水平的烟酰胺腺嘌呤二核苷酸（NAD+），一种辅因子，用作Sirtuins的底物并调节多种代谢和表观遗传分子。我们假设与杂种观察到健壮的长期肿瘤控制 Th1/17细胞是由整体改良的T细胞表型介导的，这是由于影响A的高NAD+ 包括翻译后修饰和表观遗传稳定性在内的事件的组合，导致了代谢拟合表型。鉴于NAD+在包括能量在内的多种生物过程中的关键作用代谢，衰老，钙稳态和表观基因组，我们提出以下旨在测试上述假设：目标1）确定细胞因子亚群的代谢特征和抗肿瘤表型是否杂交T1/17细胞可以翻译成编程肿瘤浸润淋巴细胞。目标2）确定是否抗体介导的CD38与PD1抗体的组合抑制作用导致抗肿瘤反应的强大抗肿瘤反应不同的临床前体内和异种移植模型；目标3）确定NAD+级别如何贡献在T1/17混合动力和CD38-KO T中保留强大的抗肿瘤响应的Metabolo-epygenetic编程细胞。我们认为，确定导致抗肿瘤的中心机制的建议混合T1/17单元的响应对于适应这些离体编程条件至关重要自适应T细胞免疫疗法中的翻译用途。