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Elucidating the Role of Tregs in Cancer Metastasis and T Cell Dysfunction

阐明 Tregs 在癌症转移和 T 细胞功能障碍中的作用

基本信息

批准号：
10679834
负责人：
Zoe Schmiechen
金额：
$ 3.26万
依托单位：
UNIVERSITY OF MINNESOTA
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：
2023-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10679834
关键词：
Ablation Adoptive Transfer Antigens Automobile Driving Biological Response Modifiers CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene CRISPR/Cas technology Cancer Etiology Cancer cell line Cell Line Cell Separation Cells Cessation of life Characteristics Combined Modality Therapy Cytotoxic T-Lymphocytes DDR2 gene Data Detection Development Disease Disseminated Malignant Neoplasm Doctor of Philosophy FOXP3 gene Flow Cytometry Functional disorder Gene Expression Profile Genes Genetic Models Goals Grant Histologic Human Immune Evasion Immune System Diseases Immune response Immunocompetent Immunologic Surveillance Immunotherapy Implant Infiltration Intrinsic factor Invaded Investigation Knock-out Knowledge Link Malignant Neoplasms Malignant neoplasm of pancreas Microscopy Modeling Mus Neoplasm Metastasis Newly Diagnosed Organ Pancreas Pancreatic Diseases Pancreatic Ductal Adenocarcinoma Patients Phenotype Population Receptor Protein-Tyrosine Kinases Regimen Regulatory T-Lymphocyte Research Research Personnel Resistance Role Signal Transduction Survival Rate T cell differentiation T-Cell Activation T-Cell Depletion T-Lymphocyte T-Lymphocyte Subsets Technical Expertise Testing Tumor Antigens Tumor Burden Tumor Cell Line Variant cancer cell cytotoxic cytotoxic CD8 T cells discoidin domain receptor 2 effective therapy exhaust exhaustion immune checkpoint blockade implantation neoantigens novel overexpression pancreatic cancer patients pancreatic ductal adenocarcinoma model prevent public health relevance retroviral transduction single-cell RNA sequencing standard of care therapeutic development therapeutic target therapy resistant transcriptome sequencing tumor tumor growth tumor microenvironment tumor progression tumor-immune system interactions

项目摘要

PROJECT ABSTRACT Pancreatic ductal adenocarcinoma (PDA) is the 4th leading cause of cancer related deaths and has a dismal 5-year survival rate of 10%. Lethality is attributed to early metastasis, late detection, and therapeutic resistance. Cytotoxic CD8 T cells are the principal mediators of immune surveillance and critical for cancer eradication. However, in PDA and other cancers, CD8 T cells progressively lose their cytotoxic function, and are thus characterized as exhausted. Immune checkpoint blockade aims to correct T cell exhaustion by blocking inhibitory signaling and has revolutionized the treatment of many malignancies. However, PDA is largely resistant. As such, this grant seeks to understand the mechanisms driving CD8 T cell exhaustion in PDA and how PDA evades an activated immune response after immunotherapy treatment. Additionally, this grant will study cancer cell-intrinsic and -extrinsic mechanisms of PDA metastasis, to develop rational therapies. My lab derived new cancer cell lines from immunotherapy resistant tumors, termed escape variants, to study mechanisms of immune evasion. I found that orthotopic implantation of escape variant cells into immunocompetent mice yields multi-organ metastatic disease, which is not seen with the immunotherapy na·1ve cell line. Thus, escape variant tumors can model metastatic disease of PDA patients. Bulk RNA sequencing identified a single gene, Ddr2, that was significantly upregulated across multiple escape variant lines compared to immunotherapy na"ive cells. Ddr2 encodes a receptor tyrosine kinase, is linked to metastasis in other malignancies, and is correlated with reduced patient survival in PDA. Investigation into the tumor microenvironment of escape variant tumors identified an accumulation of intratumoral regulatory T cells (Tregs). I found that Treg depletion significantly reduced tumor burden and metastasis and reduced the development of CD8 T cell exhaustion. I will test the central hypothesis that immunotherapy selects for metastatic cancer cells that promote intratumoral Tregs that cause CD8 T cell dysfunction. In the first Aim, I will investigate how immunotherapy escape drives Treg accumulation and metastasis. First, I will test if Treg accumulation occurs through conventional CD4 T cell differentiation within the tumor. Next, I will test if forced expression of Ddr2 drives metastasis and ablation of Ddr2 prevents metastasis. In the second Aim, I will identify the CD8 T cell subset critical for preventing PDA metastasis. First, I will determine if CD8 T cells are required for the reduction in tumor burden and abrogation of metastasis seen with Treg depletion. Next, I will use single cell RNA sequencing to identify the transcriptional signature of anti-metastatic CD8 T cells enriched with Treg depletion. Completion of the proposed research strategy will reveal mechanisms of metastasis and CD8 T cell dysfunction in PDA and identify a therapeutic target(s) in the hope of reducing PDA lethality.

项目摘要