Investigating mechanisms of peptide alarm therapy

项目概要/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。 尽管在潜在的治愈性治疗方面取得了一些成功，但许多患者没有表现出持久的反应， 需要新的方法来增强肿瘤免疫治疗。“肽报警疗法”是一种新型癌症 免疫疗法，重新利用肿瘤内的抗病毒记忆CD 8 + T细胞来驱动抗肿瘤免疫。 初次感染后，病原体特异性CD 8 + T细胞建立了一个监视程序， 遍布全身特别地，驻留记忆CD 8 + T细胞（Trm）永久地驻留在所有组织中 在初次抗原暴露后。除正常组织外，抗病毒Trm也存在于实体瘤中。 值得注意的是，与肿瘤特异性T细胞相反，肿瘤内抗病毒Trm不会耗尽，并且表现出与肿瘤特异性T细胞不同的免疫应答。 在与它们的同源抗原接合时有效的免疫激活。我们的研究表明， 在正常组织和肿瘤中的再活化导致炎性过程，包括 免疫刺激性细胞因子和趋化因子（例如IFNg、TNFa、CCL 9）的产生，以及局部 效应分子（例如抗体）和免疫细胞（例如循环记忆T细胞，NK细胞）的募集。 肿瘤内注射肽，随后再激活抗病毒Trm，诱导肿瘤 生长抑制，并表现出与免疫检查点阻断，特别是aPD-L1的协同作用。的 驱动这种抗肿瘤免疫应答的机制仍然没有被表征。在这个提议中，我将雇用 建立完善的T细胞记忆和黑色素瘤小鼠模型，以探索驱动T细胞记忆和黑色素瘤的机制。 肽报警治疗的抗肿瘤反应。目的1将确定是否病毒肽呈递通过 癌细胞是治疗功效所必需的，潜在地证明，通过肽警报疗法， 抗病毒Trm可以在肽中直接杀死癌细胞：MHCI依赖性机制。目标2将衡量和 监测肿瘤特异性T细胞和NK细胞，确定它们各自在控制肿瘤生长中的作用。 这种癌症治疗的背景。这项工作不仅将为临床前数据增加价值， 它不仅可以用于免疫疗法，而且还可以传递关于如何操纵Trm用于治疗用途的信息。 该提案将在明尼苏达大学的大卫马索普斯特博士的实验室完成， 在记忆T细胞功能和免疫监视的研究世界领先。沿着来自博士的指导。 Masopust是大学免疫学中心的协作培训环境， 医学科学家培训计划（双学位MD/PhD计划）提供的培训将作为 对我来说是一个理想的实习地点。我的长期职业目标是成为一名 作为内科临床医生推动转化研究的学术医生科学家， 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.