Impact of AICD on TCR Transduced T Cells for Adoptive Immunotherapy

AICD 对用于过继免疫治疗的 TCR 转导 T 细胞的影响

基本信息

批准号：
8555360
负责人：
Jose Alejandro Guevara-Patino
金额：
$ 29.77万
依托单位：
LOYOLA UNIVERSITY CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-21 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8555360
关键词：
Activities of Daily Living Adoptive Cell Transfers Adoptive Immunotherapy Affect CD28 gene CD8B1 gene CD94 Antigen Cell Line Cell Proliferation Cells Characteristics Clinical Trials Cues Data Dependence Development Effector Cell Equilibrium Failure Gene-Modified Goals HLA-A2 Antigen Human Immune Immune response In Vitro Individual Infusion procedures Interferons Interleukin-12 Interleukin-15 Interleukin-2 Life Malignant Neoplasms Mediating Melanoma Cell Memory Modeling Monophenol Monooxygenase Mus Patients Predisposition Production Provider Recurrence Refractory Reporting Repression Residual state Resistance Role Signal Transduction Stimulus T cell therapy T memory cell T-Cell Receptor T-Cell Receptor Genes T-Lymphocyte TNF gene Transforming Growth Factor beta Transgenic Mice Up-Regulation base cellular engineering cytokine human RGS3 protein immunogenic improved melanoma outcome forecast preconditioning progenitor response retroviral transduction trait tumor

项目摘要

In this study, we postulate that the failure of adoptive T cell therapy against recurrent melanoma may be based in part on the CD8+ T cell susceptibility to tumor-Induced suppression). Here, we show that TCR costimulation by NKG2D signaling in CD8+ T cells results in resistance to suppression by TGF-beta, augmented formation of cells resembling central memory and enhanced cytolytic function. We established a direct correlation between these traits and NKG2D co-stimulation, through upregulation of a recently described negative regulator of TGF-beta signaling in T cells, termed regulator of G-protein signaling 3 (RGS3), and repression of T-bet expression. We also found that memory CD8+ T cells express high levels of RGS3 and are resistant to tumor-induced suppression. Thus, we propose to study how NKG2D signaling in tyrosinase-reactive TCR-transduced (TIL 13831) effector and memory CD8+ T cells affects their resistance to suppression. Hypothesis 1: If NKG2D signaling in CD8+ T cells enhances cytolytic function, augments RGS3 expression and represses T-bet, then NKG2D-co-stimulated CD8+ T cells will be highly functional against tumors by acquisition of resistance to TGF-beta-mediated suppression and augmented formation of MPECs and long-term T cell memory. Hypothesis 2: If the characteristic functional response by central memory cells is faster, stronger, of longer duration and resistant to TGF-beta; then TCR-transduced CD8+ memory T cells will result in cells with similar functional abilities, and if not, then responses and resistance will be recovered by NKG2D engagement. In Specific Aim 1, we will determine how NKG2D co-stimulatory signaling in TCR transduced CD8+ T cells against melanoma affects their resistance to tumor-induced suppression, short-lived effectors and memory-progenitor effector cells formation and effector/memory development. In Specific Aim 2, we will determine how NKG2D signaling in CD8+ memory T cells serving as recipients of TCR TIL 13831 affects their resistance to tumor-induced suppression, persistence and function. We will also study the effects of NKG2D signaling in human TCR-transduced CD8+ T cells prior and after transfer into patients participating in the clinical trial

在这项研究中，我们假设养育T细胞疗法对复发性黑色素瘤的失败可能部分基于CD8+ T细胞对肿瘤诱导的抑制的敏感性）。在这里，我们表明，CD8+ T细胞中NKG2D信号传导的TCR共刺激会导致TGF-beta抑制抑制，增强了类似中心记忆的细胞形成和增强的细胞溶解功能。我们通过上调最近描述的TGF-β信号传导的负调节剂，称这些特征与NKG2D共刺激之间的直接相关性，称为G蛋白信号3（RGS3）的调节剂，以及T-Bet表达的抑制作用。我们还发现，记忆CD8+ T细胞表达高水平的RGS3，并且对肿瘤诱导的抑制有抵抗力。因此，我们建议研究酪氨酸酶反应性TCR转导（TIL 13831）效应子和记忆CD8+ T细胞中NKG2D信号传导如何影响其对抑制的抵抗力。假设1：如果CD8+ T细胞中的NKG2D信号传导增强了细胞溶解功能，增强RGS3表达并抑制T-bet，则NKG2D-CO刺激的CD8+ T细胞将通过摄取对TGF-BetA介导的抑制和抑制作用和抑制抑制作用和抑制性，对肿瘤具有很高的功能增强MPEC和长期T细胞记忆的形成。假设2：如果中央记忆细胞的特征功能响应更快，更强，持续时间更长，对TGF-beta具有抗性；然后，TCR转导的CD8+记忆T细胞将导致具有相似功能能力的细胞，如果没有，则响应和电阻将通过NKG2D参与恢复。在特定目标1中，我们将确定NKG2D在TCR转导的CD8+ T细胞中针对黑色素瘤的共刺激信号如何影响它们对肿瘤诱导的抑制，短生效的效应子和记忆 - 增生器效应细胞的形成以及效应子/记忆的发展。在特定目标2中，我们将确定CD8+记忆T细胞中的NKG2D信号传导如何作为TCR TIL 13831的受体影响它们对肿瘤诱导的抑制，持久性和功能的抵抗力。我们还将研究NKG2D信号传导对人类TCR转移的CD8+ T细胞的影响，然后转移到参加临床试验的患者中