NKG2D superagonist co-stimulation to enhance adaptive immunotherapy of cancer

摘要 有效的T细胞共刺激对于初级诱导和随后的免疫应答至关重要。 特异性T细胞反应。除了增加的共抑制信号，不足的共刺激肿瘤 抗原的维持- 微环境在很大程度上解释了肿瘤杀伤CD 8的次优激活和维持 T细胞。因此，癌症免疫治疗的主要目标之一是提供可持续的共刺激。 信号使有效的肿瘤杀伤性CD 8 T细胞的产生和持续，并最终 实现持久的肿瘤控制。然而，除了含有共刺激基序的工程化CAR-T细胞外， 工程化TCR，赋予持续原位CD 8 T细胞共刺激的手段仍然远未达到预期， 由于共刺激受体的典型和激活诱导家族的不可持续的表达 肿瘤微环境中的CD 8 T细胞。在本建议中，我们建议启动宪法上的 表达的人CD 8 T细胞共刺激受体NKG 2D与一种新的超激动剂一起扩增和维持 肿瘤抗原特异性CD 8 T细胞抗肿瘤免疫。我们假设 NKG 2D超激动剂治疗 可以通过提供可持续数量的共- 刺激以在肿瘤中诱导有效和持久的抗原特异性免疫应答。我们提出了三 具体目标：1） 描述NKG 2D超级激动剂提供可持续的 共刺激对TCR/CD 3信号传导的影响; 2）确定NKG 2D超激动剂共刺激对TCR/CD 3信号传导的影响。 3）确定过继性T细胞疗法对肿瘤治疗效果的协同或刺激作用， NKG 2D超激动剂共刺激与T细胞联合的协同癌症治疗作用 检查站封锁。假设NKG 2D超激动剂正在优化用于人类使用，如果我们的 假设被证明，该疗法可以在不久的将来转化为临床，以显着改善 癌症免疫治疗的现状。

Abstract Effective T cell co-stimulation is critical for the primary induction and subsequent specific T cell responses. In addition to increased co-inhibitory signals, insufficient co-stimulatory tumor maintenance of antigen- microenvironment accounts for a great deal of the suboptimal activation and maintenance of tumor-killing CD8 T cells. Thus, one of the major goals in the immunotherapy of cancer is to provide sustainable co-stimulatory signal to empower the generation and persistence of effective tumor-killing CD8 T cells and ultimately to achieve durable tumor control. Yet, beyond engineered CAR-T cells that contain co-stimulatory motif in the engineered TCR, means to empower sustained in situ CD8 T cell co-stimulation are still far from expectations, due to the unsustainable expression of the canonical and activation-induced family of co-stimulatory receptors on CD8 T cells in the tumor microenvironment. In this proposal, we propose to activate the constitutively expressed human CD8 T cell co-stimulatory receptor NKG2D with a novel superagonist to amplify and sustain tumor antigen-specific CD8 T cell antitumor immunity. We hypothesize that therapy with NKG2D superagonist can augment T cell-mediated immunotherapy of cancer through providing sustainable magnitude of co- stimulation to induce effective and persistent antigen-specific immune responses in tumors. We propose three Specific Aims: 1) To delineate mechanisms whereby the NKG2D superagonist provides sustainable magnitude of co-stimulation to TCR/CD3 signaling; 2) To determine the impact of the NKG2D superagonist co- stimulation on cancer therapeutic effect of adoptive T cell therapy; 3) To determine the synergistic or collaborative cancer therapeutic effect of the NKG2D superagonist co-stimulation in combination with T cell checkpoint blockades. Providing that the NKG2D superagonist is being optimized for human use, if our hypothesis is proven, the therapy can be translated into clinics in the near future to significantly improve current practice of cancer immunotherapy.