Impact of AICD on TCR Transduced T Cells for Adoptive Immunotherapy

在这项研究中，我们假设过继T细胞治疗复发性黑色素瘤的失败可能部分基于CD8+ T细胞对肿瘤诱导抑制的易感性。在这里，我们发现NKG2D信号在CD8+ T细胞中的TCR共刺激导致对tgf - β抑制的抵抗，增加了类似中枢记忆的细胞的形成，增强了细胞溶解功能。我们通过上调最近描述的T细胞中tgf - β信号的负调节因子（称为g蛋白信号3调节因子（RGS3））和抑制T-bet表达，建立了这些性状与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，并且抵抗肿瘤诱导的抑制。因此，我们建议研究酪氨酸酶反应性tcr转导（TIL 13831）效应细胞和记忆性CD8+ T细胞中的NKG2D信号如何影响它们对抑制的抗性。假设1：如果CD8+ T细胞中的NKG2D信号增强了细胞溶解功能，增加了RGS3的表达并抑制了T-bet，那么NKG2D共刺激的CD8+ T细胞将通过获得对tgf - β介导的抑制的抗性和增强mpec的形成和长期T细胞记忆而具有高抗肿瘤功能。假设2：如果中枢记忆细胞的特征性功能反应更快、更强、持续时间更长且对tgf - β有抗性；那么tcr转导的CD8+记忆T细胞将产生具有类似功能能力的细胞，如果没有，则通过NKG2D接合恢复应答和抗性。在Specific Aim 1中，我们将确定TCR转导CD8+ T细胞抗黑色素瘤的NKG2D共刺激信号如何影响它们对肿瘤诱导的抑制、短期效应和记忆祖效应细胞形成以及效应/记忆发育的抵抗。在Specific Aim 2中，我们将确定作为TCR TIL 13831受体的CD8+记忆T细胞中的NKG2D信号如何影响其对肿瘤诱导抑制的抗性、持久性和功能。我们还将研究NKG2D信号在人类tcr转导的CD8+ T细胞转移到参与临床试验的患者体内前后的影响

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