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

基本信息

批准号：
9313795
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
项目类别：
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/9313795
关键词：
Adoptive Cell Transfers Agonist Antibodies CD8-Positive T-Lymphocytes Cancer Patient Cell Differentiation process Cell Line Clinical Clinical Research Clinical Trials Cues Data Distal Effectiveness Environment Genes Genetic Transcription HLA-A2 Antigen Human Immune Immunosuppression Individual MAPK8 gene Malignant Neoplasms Mediating Mediator of activation protein Melanoma Cell Modeling Mus PDPK1 gene Pathway interactions Pharmacology Phosphotransferases RGS3 gene 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 cellular transduction experimental study genetically modified cells improved in vivo inhibitor/antagonist knock-down melanoma mutant novel overexpression protein expression public health relevance receptor response treatment response tumor tumor growth tyrosinase peptide

项目摘要

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）：经过基因修饰以表达对肿瘤抗原具有反应性的 T 细胞受体（TCR-Td T 细胞）的 T 细胞的过继细胞转移已成为治疗恶性肿瘤最有前途的方法之一。最近的临床研究报告客观的临床反应率低于 30%，研究表明，在携带肿瘤的宿主中，转移的 T 细胞遇到了以免疫抑制为特征的恶劣环境。 TCR-Td CD8+ T 细胞对这些负面环境信号具有抵抗力，可以显着改善癌症患者的临床反应。鉴于 NKG2D 受体的刺激作用，我们研究了其控制 CD8+ T 细胞抑制的能力。我们的数据首次显示 NKG2D。对人 TCR-Td CD8+ T 细胞（类似于临床试验中使用的细胞）和小鼠 CD8+ T 细胞的刺激可导致对 TGF-β 抑制的完全抵抗，并增强抗肿瘤治疗反应我们的数据还表明，NKG2D 激活的 TCR-Td CD8+ T 细胞对 TGF-β 抑制的抵抗伴随着 TGF-β 信号传导的两个负调节因子 RGS3 和 PDPK1 的上调，而这些发现描述了 NKG2D 的新功能。在 CD8+ T 细胞中，这些途径如何在 NKG2D 信号传导和抑制抵抗中相互关联仍有待确定。 TCR-Td CD8+ T 细胞的抑制是由 PI3K、Grb2 和 JNK 通路以及 RGS3 和 PDPK1 的联合作用介导的，因此，本提案的目的是剖析 NKG2D 用于赋予耐药性的近端和远端信号通路。为此，我们将使用转导表达针对酪氨酸酶的 TCR 的人和小鼠 CD8+ T 细胞。肽/HLA-A2 和 h3T 转基因小鼠，它们表达相同的受体；我们相信人类 TCR-Td CD8+ 可以通过 NKG2D 信号进行转录操纵。 T 细胞可以在 ACT 之前通过 NKG2D 激动剂轻松调节，以提高其存活率和治疗性抗肿瘤能力。