Investigating virus- and vaccine-specific T cells in glioblastoma

项目摘要/摘要 最近的研究表明，在儿童中存在大量针对病毒感染的驻留记忆T细胞(TRM) 肿瘤的范围很广，通常比癌症特异性T细胞多。因为这些细胞缺乏对肿瘤的特异性 抗原，它们免于肿瘤特异性T细胞的标志性耗尽/功能障碍。为此，我们 开发了一种新的免疫疗法，它利用免疫刺激病毒特异性的TRM功能，通过 用病毒多肽治疗以打破免疫抑制的肿瘤环境。重新激活病毒特异性 含有多肽的TRM足以抑制小鼠肿瘤的生长，当与检查点阻断相结合时， 促进了持久的肿瘤清除。清除肿瘤的小鼠受到保护，免受肿瘤的再次攻击，这表明 建立了抗肿瘤免疫。病毒特异性TRM是肿瘤免疫环境的重要组成部分。 可以在治疗上利用，但在临床上，关于 肿瘤清除的机制以及如何以最佳方式利用这些细胞。这项建议的目标是 确定(I)肿瘤细胞杀伤和持久的肿瘤免疫的机制，(Ii)病毒特异性对 TRM的功能和治疗效果，以及iii)确定重新激活病毒特异性TRM的最佳方式。vbl.使用 无论是老鼠还是人类系统，这项研究都提出了一种创新的观点，将抗病毒记忆 使用尖端细胞对肿瘤进行免疫治疗。我们将补充对小鼠的研究 组合四聚体染色，以实现对扩增的面板的T细胞的同时分析 患者肿瘤中的病毒和疫苗。这些目标的完成将促进我们对肿瘤的理解 小鼠和人的免疫监视和TRM功能，并识别新的肿瘤靶向T细胞群 免疫疗法。这一贡献预计将是重大的，因为它将提供强大的科学 框架，以扩大病毒特异性TRM治疗的有效性和实用性，并使新的 利用这些强大的免疫激活细胞的策略。

PROJECT SUMMARY/ABSTRACT Recent studies have revealed an abundance of resident memory T cells (TRM) specific for viral infections in a wide range of tumors, often outnumbering cancer-specific T cells. As these cells lack specificity to tumor antigens, they are spared from the hallmark exhaustion/dysfunction of tumor-specific T cells. To this end, we developed a novel immunotherapy which taps into immunostimulatory virus-specific TRM functions through treatment with viral peptides to break the immunosuppressive tumor environment. Reactivating virus-specific TRM with peptide was sufficient to restrict tumor growth in mice and when combined with checkpoint blockade, promoted durable tumor clearance. Mice that cleared tumors were protected from tumor re-challenge, suggesting anti-tumor immunity was established. Virus-specific TRM represent a major part of the tumor immune environment and can be leveraged therapeutically, yet there is a clinically significant gap in knowledge regarding the mechanisms of tumor clearance and how to optimally harness these cells. The objectives in this proposal are to determine (i) mechanism of tumor cell killing and durable tumor immunity, (ii) the impact of viral specificity on TRM function and therapeutic efficacy, and iii) define the optimal modality to reactivate virus-specific TRM. Using both mouse and human systems, this study addresses an innovative perspective connecting antiviral memory cells to tumor immunotherapy using cutting edge methods. We will complement mouse studies with combinatorial tetramer staining to enable simultaneous profiling of T cells specific for an expanded panel of viruses and vaccines in patient tumors. Completion of these aims will advance our understanding of tumor immunosurveillance and TRM function in mice and humans, and identify new target T cell populations for tumor immunotherapy. This contribution is expected to be significant because it will provide a strong scientific framework to expand the efficacy and utility of virus-specific TRM therapy, and enable the development of novel strategies leveraging these potent immune activating cells.