Investigating mechanisms of peptide alarm therapy

点击翻译按钮获取中文摘要

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.