Investigating mechanisms of peptide alarm therapy

项目摘要/摘要： 癌症免疫疗法将肿瘤微环境从免疫抑制转变为免疫激活。 尽管潜在治愈疗法取得了一些成功，但许多患者并没有表现出持久的反应， 需要新的方法来加强肿瘤免疫治疗。“肽报警疗法”是一种新的癌症 改变肿瘤内抗病毒记忆CD8+T细胞的用途以驱动抗肿瘤免疫的免疫疗法。 在初次感染后，病原体特异性CD8+T细胞建立一个监测程序，定位T细胞 遍及全身。特别是，常驻记忆CD8+T细胞(Trm)永久存在于所有组织中 在主要抗原暴露后。除了正常组织外，抗病毒药物Trm还存在于实体肿瘤中。 值得注意的是，与肿瘤特异性T细胞相比，肿瘤内抗病毒Trm并未耗尽并证明 当与它们的同源抗原接触时，有效的免疫激活。我们的小组表明，Trm 正常组织和肿瘤中的重新激活都会导致炎症过程，包括 产生免疫刺激细胞因子和趋化因子(如IFNG、TNFa、CCL9)，以及局部 效应分子(如抗体)和免疫细胞(如循环记忆T细胞、NK细胞)的募集。 瘤内注射多肽，以及随后抗病毒Trm的重新激活，导致肿瘤 抑制生长，并显示与免疫检查点阻断，特别是apd-L1的协同作用。这个 驱动这种抗肿瘤免疫反应的机制尚不清楚。在这份提案中，我将采用 建立T细胞记忆和黑色素瘤的小鼠模型来探索驱动T细胞记忆和黑素瘤的机制 多肽报警疗法的抗肿瘤反应。目标1将确定病毒多肽的呈现是否通过 癌细胞是治疗效果所必需的，这可能表明，通过多肽警报疗法， 抗病毒药物Trm可直接杀灭肿瘤细胞中的一种多肽：MHCI依赖机制。目标2将衡量和 监测肿瘤特异性T细胞和NK细胞，确定它们在控制肿瘤生长中的各自作用 这种癌症疗法的背景。这项工作不仅将为有前途的新的临床前数据增加价值 免疫疗法，但它也将传递有关Trm如何被操纵用于治疗的信息。 这项提案将在明尼苏达大学大卫·马索普斯特博士的实验室完成。 在研究记忆T细胞功能和免疫监控方面处于世界领先地位。此外，他还得到了Dr。 Masopust，大学免疫学中心的协作培训环境和综合 医学科学家培训计划(医学博士/博士双学位计划)提供的培训将作为 作为博士前实习生，这是我发展的理想地点。我的长期职业目标是成为一名 学术内科科学家，作为内科临床医生和 免疫学专家。

Project Summary/Abstract: Cancer Immunotherapies shift tumor microenvironments from immunosuppressive to immune-activated. Despite some success with potentially-curative treatments, many patients do not exhibit durable responses, necessitating novel approaches to enhance tumor immunotherapy. “Peptide alarm therapy” is a novel cancer immunotherapy that repurposes antiviral memory CD8+ T cells within tumors to drive antitumor immunity. After a primary infection, pathogen-specific CD8+ T cells establish a surveillance program that positions T cells throughout the entire body. In particular, resident-memory CD8+ T cells (Trm) permanently reside in all tissues after primary antigen exposure. In addition to normal tissue, antiviral Trm populate solid tumors. Notably, in contrast to tumor-specific T cells, intratumoral antiviral Trm are not exhausted and demonstrate potent immune activation upon engagement with their cognate antigen. Our group showed that Trm reactivation in both normal tissues and tumors leads to inflammatory processes, including the production of immune-stimulatory cytokines and chemokines (e.g. IFNg, TNFa, CCL9), and the local recruitment of effector molecules (e.g. antibodies) and immune cells (e.g. circulating memory T cells, NK cells). The intratumoral injection of peptide, and this subsequent reactivation of antiviral Trm, induces tumor growth suppression and exhibits synergy with immune checkpoint blockade, specifically aPD-L1. The mechanisms driving this antitumor immune response remain uncharacterized. In this proposal, I will employ well-established murine models of T cell memory and melanoma to explore the mechanisms that drive the antitumor response of peptide alarm therapy. Aim 1 will determine whether viral peptide presentation by cancer cells is necessary for treatment efficacy, potentially demonstrating that, through peptide alarm therapy, antiviral Trm can directly kill cancer cells in a peptide:MHCI-dependent mechanism. Aim 2 will measure and monitor tumor-specific T cells and NK cells, determining their respective role in controlling tumor growth in the context of this cancer therapy. Not only will this work add value to preclinical data for a promising new immunotherapy, but it will also relay information about how Trm can be manipulated for therapeutic use. This proposal will be completed at the University of Minnesota in the laboratory of David Masopust, Ph.D., a world-leader in the study of memory T cell function and immunosurveillance. Along with mentorship from Dr. Masopust, the collaborative training environment at the University’s Center for Immunology and the integrated training provided by the Medical Scientist Training Program (dual-degree MD/PhD program) will serve as an ideal location for me to develop as a predoctoral trainee. My long-term career goal is to become an academic physician scientist who drives translational research as an internal medicine clinician and specialist in immunology.