Therapeutically harnessing anti-viral resident memory T cells in solid tumors

项目总结/摘要 最近的研究表明，在一个特定的病毒感染的常驻记忆T细胞（TRM）丰富。 广泛的肿瘤，通常数量超过癌症特异性T细胞。由于这些细胞对肿瘤缺乏特异性， 抗原，它们免于肿瘤特异性T细胞的标志性耗竭/功能障碍。为此我们 开发了一种新的免疫疗法，通过以下方式利用免疫刺激病毒特异性TRM功能 用病毒肽治疗以破坏免疫抑制性肿瘤环境。再活化病毒特异性 具有肽的TRM足以限制小鼠中的肿瘤生长，并且当与检查点阻断剂组合时， 促进持久的肿瘤清除。清除肿瘤的小鼠受到保护，免受肿瘤再攻击，这表明 建立了抗肿瘤免疫。病毒特异性TRM代表肿瘤免疫环境的主要部分 并且可以在治疗上加以利用，但是在关于 肿瘤清除机制以及如何最佳地利用这些细胞。本提案的目标是 确定（i）肿瘤细胞杀伤和持久肿瘤免疫的机制，（ii）病毒特异性对肿瘤细胞的影响， TRM功能和治疗功效，以及iii）定义重新激活病毒特异性TRM的最佳模式。使用 无论是小鼠和人类系统，这项研究提出了一个创新的观点，连接抗病毒记忆 细胞到肿瘤免疫疗法使用尖端方法。我们将补充小鼠研究， 组合四聚体染色，以能够同时分析对扩增的一组T细胞特异性的T细胞。 病毒和疫苗。这些目标的实现将促进我们对肿瘤的认识 免疫监视和TRM功能，并鉴定肿瘤新靶T细胞群 免疫疗法预计这一贡献将是重大的，因为它将提供一个强有力的科学 框架，以扩大病毒特异性TRM治疗的功效和效用，并使新的 利用这些有效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.