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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结/文摘