Profiling and leveraging bystander T cells within the tumor microenvironment

分析和利用肿瘤微环境中的旁观者 T 细胞

基本信息

批准号：
10573231
负责人：
NICHOLAS JOSEPH MAURICE
金额：
$ 9.04万
依托单位：
UNIVERSITY OF MINNESOTA
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：
2022-02-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10573231
关键词：
3-Dimensional Ablation Activities of Daily Living Adaptive Immune System Adoptive Transfer Age Anatomy Animal Model Antigen Presentation Antigens Antitumor Response Autoimmunity Blocking Antibodies Bystander Effect CD8-Positive T-Lymphocytes CTLA4 gene CXCR3 gene Cancer Model Cause of Death Cell Surface Proteins Cells Cessation of life Chronic Color Complement Cytolysis Diagnosis Disease Excision Failure Flow Cytometry Functional disorder Goals Homeostasis Human Immune Immune Targeting Immune response Immune system Immunofluorescence Immunologic Immunotherapy Impairment Infiltration Inflammation Interferon Type II Intervention Knock-out Lead Ligation Major Histocompatibility Complex Malignant Neoplasms Mediating Methods Mission Modality Natural Killer Cells Outcome Outcomes Research Pathogenesis Patients Phase Phenotype Play Population Positioning Attribute Process Proteins Radiation Receptor Signaling Relapse Research Role Second Primary Cancers Solid Neoplasm Specificity Stress Surveys T cell response T-Cell Activation T-Cell Receptor T-Lymphocyte Testing Therapeutic Tissues Toxic effect Transgenic Organisms Transplantation Tumor Antigens Tumor Promotion Tumor-Infiltrating Lymphocytes United States National Institutes of Health Up-Regulation Work anti-tumor immune response antigen-specific T cells cancer immunotherapy cancer infiltrating T cells cancer therapy cell motility chemokine receptor chemotherapy chimeric antigen receptor chimeric antigen receptor T cells chronic infection congenic conventional therapy cytokine cytotoxic design exhaustion experimental study genetically modified cells immune checkpoint blockade improved inhibitor migration mortality mouse model neoplasm immunotherapy neoplastic cell programmed cell death protein 1 receptor receptor binding recruit response side effect standard of care success tool tumor tumor heterogeneity tumor microenvironment tumor specificity

项目摘要

PROJECT SUMMARY/ABSTRACT Cancer remains a leading cause of mortality within the US, responsible for 1 in 4 deaths. Immunotherapies have ushered in a new age of cancer treatment, leveraging the potency of the immune system to restrict cancer without many of the side effects of conventional therapies. These immunotherapies have primarily targeted immune responses specific for tumor antigens (tAg). Although tAg-specific T cell immunotherapies have proven powerful tools in combatting cancer, their success is context-dependent, displaying limited efficacy in most solid tumors. This is largely owed to chronic T cell receptor (TCR) binding to cognate tAg, leading to permanent cellular dysfunction. Solid tumors comprise the majority of cancer cases and deaths, thus, it is essential to exploit other cellular modalities in immunotherapies. Recently, it has become apparent that tAg-nonspecific “bystander” T cells are observed and often outnumber tAg-specific T cells in solid tumors. Although their function within tumors is unknown, bystander T cells can exert cytotoxic effector function once activated by inflammation in a number of contexts. My unique approach leveraging T cells with defined T cell receptors (TCRs) allows me to determine the mechanisms that dictate bystander T cell entry into the tumor and if they maintain the ability to respond to stimulation once tumor-resident. To appreciate the heterogeneity of tumor microenvironments, I will employ multiple animal models of solid tumors. My objectives are two-fold: First, I want to test how bystander T cells migrate to the tumor and if they are spared from dysregulation due to their inability to recognize tAg. Second, I want to test if the dichotomous effects of bystander T cells can be therapeutically leveraged to improve anti- tumor responses. At homeostasis, bystander T cells can simply deny other immune cells access to targets, hindering antigen (Ag)-specific immune responses. Once activated by inflammation, bystander T cells rapidly acquire effector function and directly kill target cells in an innate-like manner. To achieve these objectives, I will employ my expertise in 28-color flow cytometry to interrogate cell phenotype, activation, and functional capacity. I will complement my use of flow cytometry with 3-dimensional immunofluorescence, which will uncover sub- anatomic immune cell organization within the tumor. Hypothesis: My central hypothesis is that bystander T cells in solid tumors remain functional and can be therapeutically leveraged in cancer specifically. I will test this hypothesis through two independent aims: AIM 1: Test the hypothesis that bystander T cells are recruited into tumors by CXCR3 and remain functional in the tumor microenvironment. AIM 2: Test the hypothesis that anti- tumor immune responses can be enhanced by activated bystander T cells or targeted depletion of tissue-resident bystanders. My proposed experiments will elucidate the role of bystander T cells in tumor both with and without interventions, with the goal of developing interventions to improve cancer outcomes, which is in alignment with the mission of the NCI and NIH.

项目概要/摘要癌症仍然是美国死亡的主要原因，四分之一的死亡是由免疫疗法造成的。开创了癌症治疗的新时代，利用免疫系统的效力来限制癌症，而无需传统疗法的许多副作用主要针对免疫。尽管 tAg 特异性 T 细胞免疫疗法已被证明是有效的。抗癌工具，其成功与否取决于具体情况，在大多数实体瘤中显示出有限的功效。这主要是由于慢性 T 细胞受体 (TCR) 与同源 tAg 结合，导致永久性细胞损伤实体瘤占癌症病例和死亡的大多数，因此，有必要利用其他方法。最近，tAg 非特异性“旁观者”T 的作用已变得显而易见。尽管它们在肿瘤内发挥作用，但在实体瘤中观察到 TAg 细胞的数量通常超过 tAg 特异性 T 细胞。目前尚不清楚，旁观者 T 细胞一旦被炎症激活，就可以发挥细胞毒性效应功能我利用具有特定 T 细胞受体 (TCR) 的 T 细胞的独特方法使我能够确定决定旁观者 T 细胞进入肿瘤的机制以及它们是否保持响应能力为了了解肿瘤微环境的异质性，我将采用肿瘤驻留后的刺激。我的目标有两个：首先，我想测试旁观者 T 细胞的作用。迁移到肿瘤，如果它们由于无法识别 tAg 而免于失调。想要测试是否可以利用旁观者 T 细胞的二分效应来改善抗- 在稳态时，旁观者 T 细胞可以简单地拒绝其他免疫细胞接近目标，一旦被炎症激活，旁观者 T 细胞就会迅速阻碍抗原 (Ag) 特异性免疫反应。获得效应器功能并以与生俱来的方式直接杀死靶细胞为了实现这些目标，我将。利用我在 28 色流式细胞术方面的专业知识来询问细胞表型、激活和功能能力。我将用 3 维免疫荧光补充我对流式细胞术的使用，这将揭示亚肿瘤内的解剖免疫细胞组织假设：我的中心假设是旁观者 T 细胞。在实体瘤中仍然具有功能并且可以在癌症中发挥作用，我将对此进行具体测试。通过两个独立目标的假设：目标 1：检验旁观者 T 细胞被招募到的假设 CXCR3 抑制肿瘤并在肿瘤微环境中保持功能 AIM 2：检验抗-CXCR3 的假设。激活旁观者 T 细胞或靶向消除组织驻留细胞可增强免疫肿瘤反应我提出的实验将阐明旁观者 T 细胞在有或无肿瘤中的作用。干预措施，旨在制定干预措施以改善癌症结果，这与 NCI 和 NIH 的使命。