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

在这项研究中，我们假设过继性T细胞治疗复发性黑色素瘤的失败可能部分基于CD 8 + T细胞对肿瘤诱导的抑制的易感性。在这里，我们表明，在CD 8 + T细胞中，NKG 2D信号转导的TCR共刺激导致对TGF-B抑制的抵抗，类似于中央记忆的细胞的形成增强和细胞溶解功能增强。我们通过上调最近描述的T细胞中TGF-β信号传导的负调节因子（称为G蛋白信号传导调节因子3（RGS 3））和抑制T-bet表达，建立了这些性状与NKG 2D共刺激之间的直接相关性。我们还发现，记忆性CD 8 + T细胞表达高水平的RGS 3，并且对肿瘤诱导的抑制具有抗性。因此，我们建议研究酪氨酸酶反应性TCR转导（TIL 13831）的效应和记忆CD 8 + T细胞中的NKG 2D信号传导如何影响其对抑制的抗性。假设1：如果CD 8 + T细胞中的NKG 2D信号传导增强细胞溶解功能，增强RGS 3表达并抑制T-bet，则NKG 2D共刺激的CD 8 + T细胞将通过获得对TGF-β介导的抑制的抗性以及增强MPEC的形成和长期T细胞记忆而具有高度的抗肿瘤功能。假设二：如果中央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-B具有抗性;那么TCR转导的CD 8+记忆T细胞将产生具有相似功能能力的细胞，如果不是，那么反应和抗性将通过NKG 2D参与恢复。在特定目标1中，我们将确定TCR转导的CD 8 +T细胞中抗黑色素瘤的NKG 2D共刺激信号传导如何影响其对肿瘤诱导的抑制、短寿命效应子和记忆祖细胞效应细胞形成以及效应子/记忆发育的抗性。在特定目标2中，我们将确定作为TCR TIL 13831受体的CD 8+记忆T细胞中的NKG 2D信号传导如何影响其对肿瘤诱导的抑制、持久性和功能的抵抗。我们还将研究转移至参与临床试验“ACT与TCR（TIL 1383 l）转导的T细胞抗黑色素瘤”的患者体内前后，人TCR转导的CD 8 + T细胞中NKG 2D信号传导的影响。"

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-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."