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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.

摘要最近的临床前研究表明，辅助性CD4+T辅助细胞(Th)和CD8+细胞的不同亚群 T细胞毒性(TC)细胞有望在过继细胞治疗(ACT)方案中得到临床应用。重要的是，T 具有分泌IL-17(Th17)能力的辅助细胞亚群已被证明具有干细胞样表型，归因于它们的长期持久性，并导致肿瘤控制的改善，如与Th1亚群(分泌干扰素γ、白介素2、肿瘤坏死因子α)比较。然而，与这些观察相反的是，有报道称，与Tc17细胞相比，Tc1细胞表现出更好的肿瘤控制能力。T细胞的这些差异在抑制性肿瘤微环境中，亚群对控制肿瘤的反应是复杂的很大一部分肿瘤反应性T细胞获得FoxP3+调节表型，变得功能障碍或经历细胞死亡，导致肿瘤逆转。因此，体外编程条件可以使T细胞成为稳定的表型，不仅能控制原发肿瘤，还能形成抗肿瘤记忆对于ACT来说将是极其重要的。我们最近确定了编程条件将Th1细胞的“抗肿瘤效应功能”和Th17细胞的“干细胞性”结合在一起，可以产生更好的表现出长期肿瘤控制的混合Th1/17细胞。重要的是，这些体外编程条件也产生高效的Tc1/Tc17杂交细胞并产生人肿瘤浸润性淋巴细胞细胞因子分泌能力增强。重要的是，杂交T细胞表现出更高水平的烟酰胺腺二核苷酸(NAD+)，一种辅因子，作为sirtuins的底物，调节多种代谢和表观遗传分子。我们假设用杂交药观察到了强健的长期肿瘤控制 Th1/17细胞是由高NAD+导致的T细胞表型全面恢复所介导的。包括翻译后修饰和表观遗传稳定性在内的事件组合导致符合新陈代谢的表型。鉴于NAD+在包括能源在内的各种生物过程中的关键作用新陈代谢、衰老、钙稳态和表观基因组，我们提出以下目的来检验上述问题假设：目的1)确定细胞因子亚群的代谢特征和抗肿瘤表型杂交T1/17细胞可以被转化为编程肿瘤浸润性淋巴细胞；目的2)确定抗体介导的CD38与PD1抗体的联合抑制在小鼠体内产生强大的抗肿瘤反应不同的临床前活体和异种移植模型；以及目的3)确定NAD+水平如何对代谢-表观遗传规划在T1/17杂交瘤和CD38-KO T中保持强大的抗肿瘤反应细胞。我们认为，这项确定导致卓越抗肿瘤作用的中心机制的提议杂交T1/17细胞的反应对于适应这些体外编程条件将是重要的翻译在过继T细胞免疫治疗中的应用。