Rescuing Anti-tumor Responses of TCR-Td T Cells by NKG2D-stimulation

通过 NKG2D 刺激挽救 TCR-Td T 细胞的抗肿瘤反应

• 批准号: 8909077
• 负责人: Jose Alejandro Guevara-Patino
• 金额: $ 31.33万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-08 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8909077
• 关键词: Adoptive Cell Transfers; Agonist; Antibodies; CD8B1 gene; Cancer Patient; Cell Line; Cells; Clinical; Clinical Research; Clinical Trials; Cues; Data; Distal; Effectiveness; Environment; Genes; HLA-A2 Antigen; Health; Human; Immune; Immunosuppression; Individual; MAPK8 gene; Malignant Neoplasms; Mediating; Mediator of activation protein; Melanoma Cell; Modeling; Mus; PDPK1 gene; Pathway interactions; Phosphotransferases; Reporting; Resistance; Role; Signal Pathway; Signal Transduction; System; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Time; Transgenic Mice; Tumor Antigens; Tumor Immunity; Up-Regulation; Work; human RGS3 protein; improved; in vivo; inhibitor/antagonist; melanoma; mutant; novel; overexpression; protein expression; receptor; research study; response; tumor; tumor growth; tyrosinase peptide

DESCRIPTION (provided by applicant): Adoptive cell transfer of T cells genetically modified to express a T cell receptor reactive to a tumor antigen (TCR-Td T cells) has emerged as one of the most promising approaches for the treatment of malignancies. However, recent clinical studies report objective clinical response rates lower than 30%. Providing a plausible explanation for these responses, studies have shown that, in tumor-bearing hosts, transferred T cells encounter an inhospitable environment characterized by immune suppression. Hence, rendering TCR-Td CD8+ T cells resistant to these negative environmental cues could significantly improve clinical responses in cancer patients. Given the stimulatory role of the NKG2D receptor, we investigated its ability to control CD8+ T cell suppression. Our data show for the first time that NKG2D stimulation in human TCR-Td CD8+ T cells (similar to those used in clinical trials) and mouse CD8+ T cells results in complete resistance to suppression by TGF-� and augmented therapeutic anti-tumor responses against melanoma. Our data also show that NKG2D-activated TCR-Td CD8+ T cell resistance to suppression by TGF-� is accompanied by the upregulation of two negative regulators of TGF-� signaling, RGS3 and PDPK1. While these findings depict novel functions for NKG2D in CD8+ T cells, how these pathways are interconnected in NKG2D signaling and resistance to suppression remains to be determined. We hypothesize that NKG2D-induced resistance of TCR-Td CD8+ T cells to suppression is mediated by the PI3K, Grb2, and JNK pathways and the combined effects of RGS3 and PDPK1. Thus, the objective of this proposal is to dissect the proximal and distal signaling pathways utilized by NKG2D to confer resistance to TGF-� and enhanced anti-tumor immunity. To do this, we will use human and mouse CD8+ T cells transduced to express a TCR against a tyrosinase peptide/HLA-A2 and h3T transgenic mice, which express the same receptor. Our study posits a new paradigm; human CD8+ T cells can be transcriptionally manipulated by NKG2D signaling to achieve resistance to TGF-�. We believe that human TCR-Td CD8+ T cells could be easily conditioned prior to ACT by an NKG2D agonist to enhance their survival and therapeutic anti-tumor capacity.

描述(由申请人提供)：T细胞过继细胞转移(TCR-TD T细胞)是治疗恶性肿瘤最有希望的方法之一。然而，最近的临床研究报告客观的临床缓解率低于30%。研究为这些反应提供了一个合理的解释，研究表明，在荷瘤宿主中，被转移的T细胞遇到了以免疫抑制为特征的不适宜居住的环境。因此，使TCR-TD CD8+T细胞抵抗这些负面环境信号可以显著改善癌症患者的临床反应。考虑到NKG2D受体的刺激作用，我们研究了它控制CD8+T细胞抑制的能力。我们的数据首次显示，NKG2D刺激人TCR-TD CD8+T细胞(类似于临床试验中使用的细胞)和小鼠CD8+T细胞可以完全抵抗转化生长因子-�的抑制，并增强对黑色素瘤的治疗抗肿瘤反应。我们的数据还表明，NKG2D激活的TCR-TD CD8+T细胞对转化生长因子-�抑制的抵抗伴随着转化生长因子-�信号的两个负调控因子RGS3和PDPK1的上调。虽然这些发现描绘了NKG2D在CD8+T细胞中的新功能，但这些通路如何在NKG2D信号和抵抗抑制中相互联系仍有待确定。我们推测NKG2D诱导的TCR-TD CD8+T细胞对抑制的抵抗是由PI3K、Grb2和JNK通路以及RGS3和PDPK1的联合作用所介导的。因此，这项建议的目的是剖析NKG2D用来抵抗转化生长因子-�和增强抗肿瘤免疫的近端和远端信号通路。为此，我们将使用转化的人和小鼠CD8+T细胞来表达针对酪氨酸酶多肽/人类白细胞抗原A2和H3T转基因小鼠的TCR，这些转基因小鼠表达相同的受体。我们的研究假设了一种新的范式：人类CD8+T细胞可以通过NKG2D信号在转录上操纵来实现对转化生长因子-�的抵抗。我们相信，人TCR-TD CD8+T细胞在ACT前可以很容易地被NKG2D激动剂调节，以提高其存活率和治疗抗肿瘤能力。