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CTL-killing capacity and cancer stiffness in cancer immunity and therapy

癌症免疫和治疗中的 CTL 杀伤能力和癌症硬度

基本信息

批准号：
10274980
负责人：
WEIPING ZOU
金额：
$ 64.74万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-07 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10274980
关键词：
Aerobic Affect Air Movements Amino Acid Transporter Amino Acids Attention Biological Biomechanics Breast Cancer Cell CD8-Positive T-Lymphocytes Cell Proliferation Cell membrane Cells Characteristics Chemoresistance Cytoplasmic Granules DNA Sequence Alteration Data Development Effector Cell Elasticity Epigenetic Process Event FOXP3 gene Genetic Glutamine Goals Granzyme Human Hypoxia Immune Immune Evasion Immune response Immune system Immunity Immunization Immunologics Immunology Immunotherapeutic agent Immunotherapy Impairment Interferons Light Link Lytic Malignant Neoplasms Measurement Mechanics Mediating Mediator of activation protein Membrane Metabolic Metabolism Microscope Molecular Mus Mutation Myeloid-derived suppressor cells Myosin Type II Nature Neoplasm Metastasis Oncology Pathology Pathway interactions Patient-Focused Outcomes Patients Phenotype Process Regulation Regulatory T-Lymphocyte Research Resistance Role Scanning Probe Microscopes Signal Pathway Solid Neoplasm Spectrometry, Mass, Electrospray Ionization T-Lymphocyte Techniques Testing Tissues Tumor Immunity Tumor-infiltrating immune cells Warburg Effect aerobic glycolysis amino acid metabolism base cancer cell cancer genetics cancer stem cell cancer therapy cell killing cytotoxic cytotoxic CD8 T cells effector T cell empowered imaging system immune checkpoint blockade immune resistance interdisciplinary approach laser tweezer mass spectrometric imaging neoplasm immunotherapy neoplastic cell novel perforin resistance mechanism stem-like cell stemness tool tumor tumor metabolism tumor microenvironment uptake

项目摘要

Project Summary/Abstract: CD8+ T cells (CTLs) mediate protective tumor immunity. The goal of tumor immune therapy is to engender long-term protective effector T cell immunity and cause tumor eradiation in patients with cancer. To this end, tumor cells must be receptive and susceptible to CTL-mediated tumor killing. However, in addition to the quality and quantity of CTLs, what determines tumor cell receptivity to CTL- mediated tumor killing is poorly understood. It is essential to conduct comprehensive molecular and functional research on the nature of tumor cell receptivity to CTLs in the human tumor microenvironment. Tumor biologists have been working on how tumor metabolism enables tumor cell proliferation, survival, and invasiveness without a comprehensive consideration of the immune involvement. Recent immunological studies have started to examine how tumor metabolism affects the phenotype and function of different immune cell subsets in the tumor microenvironment. Yet, how tumor metabolism affects tumor cell receptivity to CTL- killing is basically unknown. Having established an Optical Tweezers Microscope (OTM) technique and Atomic Force Microscope (AFM) for cell elasticity and stiffness measurements and applied an airflow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI), we are able to preliminarily demonstrate that human and mouse breast tumor cells empowered with particular amino acid uptake resulted in reduced myosin II-mediated contractile activation and tumor cell stiffness. Loss of tumor stiffness led to tumor cell membrane resistance to perforin drilling force and pore formation by CTLs, resulting in impaired T cell-mediated tumor killing. Mechanistically, tumor cells were addicted to certain amino acids, including glutamine, via high expression of SLC6A14, a glutamine transporter. Interestingly, tumor SLC6A14 expression was controlled by hypoxia. These data reveal previously unknown mechanisms of connection between specific amino acid metabolism, hypoxia, and T cell immunity in the tumor microenvironment, thereby identifying cancer glutamine transporter(s) as a potential novel immune metabolic checkpoint target. Based on these surprising and novel findings, we hypothesize that cancer cell stiffness determines tumor cell receptivity to CTL-killing, and the interplay between hypoxia and particular amino acid uptake is a novel immune evasion mechanism in the tumor microenvironment. We propose two specific aims and 8 subaims to test our central hypothesis that hypoxia targets tumor amino acid transporters, exemplified by SLC6A14, to alter tumor cell receptivity to CTL-killing and tumor immunity and therapy. Our specific aims are: Aim 1 is to test our hypothesis that hypoxia metabolically weakens tumor receptivity to CTL-killing. Aim 2 is to test our hypothesis that hypoxia mechanically weakens tumor receptivity to CTL-killing.

项目摘要/摘要：CD8+ T细胞介导肿瘤保护性免疫。肿瘤的目标