IMPACT OF IMMUNE SUPPRESSION ON TCR-TRANSDUCED T CELLS FOR ADOPTIVE

免疫抑制对 TCR 转导 T 细胞过继的影响

• 批准号: 8744934
• 负责人: MICHAEL I. NISHIMURA
• 金额: $ 20.53万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-04 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8744934
• 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; Immunosuppression; In Vitro; Individual; Infusion procedures; Instruction; Interferons; Interleukin-12; Interleukin-15; Interleukin-2; Interleukin-7; 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; Transgenic Mice; Up-Regulation; base; cellular engineering; cytokine; human RGS3 protein; immunogenic; improved; melanoma; outcome forecast; preconditioning; progenitor; response; retroviral transduction; trait; tumor

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-B, 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-B 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 tyrosinasereactive 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-P-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-B; 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 "ACT with TCR (TIL 1383l)-transduced T cells against melanoma."

在这项研究中，我们假设过继T细胞疗法治疗复发黑色素瘤的失败可能部分基于CD8+T细胞对肿瘤诱导抑制的敏感性)。在这里，我们发现，在CD8+T细胞中，NKG2D信号的TCR共刺激导致抵抗转化生长因子-β的抑制，增加类似中央记忆的细胞的形成，并增强细胞溶解功能。我们通过上调T细胞中最近被描述的转化生长因子-B信号的负调控因子，称为G蛋白信号调节因子3(RGS3)，并抑制T-bet的表达，建立了这些特征与NKG2D共刺激之间的直接关联。我们还发现，记忆性CD8+T细胞表达高水平的RGS3，并对肿瘤诱导的抑制具有抵抗力。因此，我们建议研究NKG2D信号在酪氨酸激活的TCR转导(TIL 13831)效应细胞和记忆性CD8+T细胞中如何影响其对抑制的抵抗力。假设1：如果CD8+T细胞中的NKG2D信号增强细胞溶解功能，增强RGS3的表达并抑制T-bet，那么NKG2D共刺激的CD8+T细胞将获得对转化生长因子-β介导的抑制的抵抗力，并增强MPECs的形成和长期T细胞记忆，从而具有高度的抗肿瘤功能。假设2：如果中央记忆细胞的特征功能反应更快、更强、持续时间更长、对转化生长因子-β具有抵抗力，那么TCR转导的CD8+记忆T细胞将导致具有类似功能的细胞，如果不是，则NKG2D参与将恢复反应和抵抗力。在特定的目标1中，我们将确定TCR转导的CD8+T细胞中的NKG2D共刺激信号如何影响它们对肿瘤诱导的抑制、短期效应和记忆-祖细胞效应细胞的形成以及效应/记忆的发展。在特定的目标2中，我们将确定作为TCRTIL 13831受体的CD8+记忆性T细胞中的NKG2D信号如何影响其对肿瘤诱导抑制的抵抗力、持久性和功能。我们还将研究NKG2D信号在TCR(TIL 1383l)转导的T细胞抗黑色素瘤的临床试验患者体内转移前后NKG2D信号的作用。