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

利用抗病毒驻留记忆 T 细胞治疗实体瘤

• 批准号: 10586695
• 负责人: Pamela Rosato
• 金额: $ 50.67万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586695
• 关键词: 2019-nCoV; Address; Automobile Driving; Blood Tests; CD8-Positive T-Lymphocytes; Cell physiology; Cells; Cellular immunotherapy; Clinic; Clinical; Complement; Cytomegalovirus; Data; Detection; Development; Environment; Epstein-Barr Virus Infections; Functional disorder; Human; Human Herpesvirus 4; Immune; Immunologic Surveillance; Immunologics; Immunotherapy; Infection; Inflammatory; Influenza A virus; Knowledge; Malignant Neoplasms; Memory; Messenger RNA; Methods; Modality; Modeling; Mus; Natural Immunity; Patients; Peptides; Population; Predisposition; Production; Resistance; Slice; Solid Neoplasm; Specificity; Stains; System; T-Lymphocyte; Testing; Therapeutic; Tissues; Translations; Treatment Efficacy; Tumor Antigens; Tumor Immunity; Vaccines; Viral; Viral Antigens; Virus; Virus Diseases; Work; adaptive immune response; adaptive immunity; anti-PD-L1; cancer immunotherapy; cell killing; clinical translation; clinically significant; combinatorial; cytokine; cytotoxic; exhaustion; human model; immune checkpoint blockade; in vivo; influenza infection; innovation; melanoma; mouse model; neoplasm immunotherapy; neoplastic cell; novel; novel strategies; pathogen; programmed cell death ligand 1; recruit; targeted treatment; tissue resident memory T cell; translational therapeutics; tumor; tumor growth

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.

项目概要/摘要 最近的研究表明，体内存在大量针对病毒感染的常驻记忆 T 细胞 (TRM)。 广泛的肿瘤，通常超过癌症特异性 T 细胞。由于这些细胞缺乏针对肿瘤的特异性 抗原，它们不会出现肿瘤特异性 T 细胞的标志性耗竭/功能障碍。为此，我们 开发了一种新型免疫疗法，通过以下方式利用免疫刺激病毒特异性 TRM 功能 用病毒肽治疗以打破免疫抑制肿瘤环境。重新激活病毒特异性 含有肽的 TRM 足以限制小鼠体内的肿瘤生长，并且当与检查点阻断相结合时， 促进持久的肿瘤清除。清除肿瘤的小鼠免受肿瘤的再次攻击，这表明 建立了抗肿瘤免疫力。病毒特异性 TRM 代表肿瘤免疫环境的主要部分 并且可以在治疗上利用，但临床上在这方面的知识还存在重大差距 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）肿瘤细胞杀伤机制和持久的肿瘤免疫，（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 的最佳方式。使用 无论是小鼠还是人类系统，这项研究提出了连接抗病毒记忆的创新视角 使用尖端方法进行细胞肿瘤免疫治疗。我们将补充小鼠研究 组合四聚体染色可同时对扩展的一组 T 细胞进行分析 患者肿瘤中的病毒和疫苗。完成这些目标将增进我们对肿瘤的理解 小鼠和人类的免疫监视和 TRM 功能，并确定肿瘤的新靶 T 细胞群 免疫疗法。预计这一贡献将是重大的，因为它将提供强有力的科学依据 框架，以扩大病毒特异性 TRM 疗法的功效和效用，并促进新型药物的开发 利用这些有效的免疫激活细胞的策略。