Investigating mechanisms of peptide alarm therapy

研究肽警报疗法的机制

• 批准号: 10425397
• 负责人: Noah Veis Gavil
• 金额: $ 4.2万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10425397
• 关键词: Adaptive Immune System; Agonist; Alleles; Antibodies; Antigens; Antitumor Response; Automobile Driving; Binding; Biological Assay; Blood; CD8-Positive T-Lymphocytes; CD8B1 gene; CRISPR/Cas technology; CTLA4 gene; Cancer cell line; Cell Line; Cell physiology; Cells; Cellular biology; Cessation of life; Clinical; Cytomegalovirus; Data; Doctor of Philosophy; Engineering; Environment; Exercise; Exhibits; Goals; Histocompatibility Antigens Class I; Human; Human Herpesvirus 4; Immune; Immune system; Immunologic Surveillance; Immunologics; Immunology; Immunotherapy; Inflammatory; Influenza; Injections; Interferons; Internal Medicine; Laboratories; Licensing; Location; MHC Class I Genes; Measures; Mediating; Medical; Melanoma Cell; Memory; Mentorship; Metastatic Melanoma; Minnesota; Modeling; Monitor; Mus; Natural Killer Cells; Normal tissue morphology; Oral mucous membrane structure; Patients; Peptide/MHC Complex; Peptides; Peripheral; Physicians; Positioning Attribute; Primary Infection; Process; Production; Recording of previous events; Resistance; Role; Scientist; Sentinel; Skin; Solid Neoplasm; Specialist; Specificity; Structure of parenchyma of lung; Surveillance Program; System; T memory cell; T-Cell Immunologic Specificity; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic Uses; Tissues; Training; Training Programs; Translational Research; Transplantation; Treatment Efficacy; Tumor Antigens; Tumor Immunity; Tumor-Infiltrating Lymphocytes; Universities; Variant; Viral; Virus; Virus Diseases; Work; anti-PD-L1; anti-tumor immune response; arm; cancer cell; cancer immunotherapy; cancer therapy; career; cell type; chemokine; curative treatments; cytokine; cytotoxic; flu; immune activation; immune checkpoint blockade; influenza infection; melanoma; mouse model; neoplasm immunotherapy; neoplastic cell; novel; novel strategies; novel therapeutics; pathogen; pathogenic virus; pre-clinical; pre-doctoral; programmed cell death protein 1; programs; protein complex; recruit; response; success; synergism; tumor; tumor growth; tumor-immune system interactions

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.

项目总结/文摘: