NKG2D superagonist co-stimulation to enhance adaptive immunotherapy of cancer

摘要 有效的T细胞共刺激对于初始诱导和后续的诱导至关重要 特异性T细胞反应。除了共抑制信号增加外，共刺激作用不足的肿瘤 抗原的维持- 微环境在很大程度上解释了杀瘤CD8的激活和维持不理想 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 增强有效的肿瘤杀伤CD8 T细胞的产生和持续的信号，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CAR-T细胞外， 经过改造的TCR，实现持续原位CD8 T细胞共刺激的方法仍远未达到预期， 由于规范和激活诱导的共刺激受体家族的不可持续的表达 对肿瘤微环境中CD8T细胞的影响。在这项建议中，我们建议在宪法上激活 新型超激动剂诱导表达人CD8T细胞共刺激受体NKG2D扩增和维持 肿瘤抗原特异性CD8T细胞抗肿瘤免疫。我们假设 NKG2D超激动剂治疗 可通过提供可持续数量的共刺激分子来增强T细胞介导的癌症免疫治疗 在肿瘤中诱导有效和持久的抗原特异性免疫反应的刺激。我们提出三个建议 具体目标：1) 描述NKG2D超级激动剂提供可持续的 共刺激对TCR/CD3信号的影响；2)确定NKG2D超级激动剂对TCR/CD3信号通路的影响 过继T细胞疗法对肿瘤治疗效果的刺激；3)测定其协同效应或 NKG2D超激动剂联合T细胞协同治疗肿瘤的实验研究 检查站封锁。假设NKG2D超级激动剂正在为人类使用进行优化，如果我们的 假设得到证实，该疗法可在不久的将来转化为临床显著改善 目前癌症免疫治疗的实践。

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.