Interrogating the Fgl2-FcgRIIB axis: A novel mechanism mediating apoptosis of tumor-specific memory CD8+ T cells

探究 Fgl2-FcgRIIB 轴：介导肿瘤特异性记忆 CD8 T 细胞凋亡的新机制

基本信息

批准号：
10743485
负责人：
Kelsey Bennion
金额：
$ 4.92万
依托单位：
EMORY UNIVERSITY
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：
2023-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10743485
关键词：
American Antitumor Response Apoptosis Binding CASP3 gene CD8-Positive T-Lymphocytes Cancer Patient Cell Separation Cell Survival Cell secretion Cells Characteristics Cutaneous Melanoma Cytoplasmic Tail Data Diagnosis Disease Exhibits FOXP3 gene Fc Receptor Fibrinogen Flow Cytometry Future Gene set enrichment analysis Goals Grant Hematopoietic Homeostasis Human ITIM Immune Immune response Immunity Immunotherapeutic agent Immunotherapy Induction of Apoptosis Infiltration Inflammatory Institution Interferon Type II Investigation Knock-out Label Ligand Binding Ligands Malignant Neoplasms Mediating Memory Modeling Molecular Mus Pathway interactions Patient-Focused Outcomes Patients Peptides Phenotype Population Postdoctoral Fellow Production Prognostic Marker Protein Secretion Proteins Proteomics Publications RNA Regulation Regulatory T-Lymphocyte Research Resistance Role Sampling Signal Transduction Skin Skin Cancer Source Surface T cell response T-Cell Receptor T-Lymphocyte TNF gene Transgenic Mice Transgenic Organisms Work autocrine cancer immunotherapy cancer infiltrating T cells cell type cytokine cytotoxic CD8 T cells exhaust fighting improved melanoma mouse model multiple omics novel patient response programmed cell death protein 1 receptor receptor binding recruit resistance mechanism response response biomarker single-cell RNA sequencing success therapeutic target transcriptomics transmission process tumor tumor microenvironment

项目摘要

PROJECT SUMMARY One in fifty Americans will be diagnosed with melanoma in their lifetime and skin cutaneous melanoma is the deadliest skin cancer. Cancer immunotherapy is a breakthrough approach to treat this disease and cytotoxic CD8+ T-cell tumor infiltration is a critical factor to immunotherapeutic success. As such, identifying effective strategies to increase the magnitude and functionality of the patient’s tumor-specific CD8+ T-cell response remains an important goal. Inhibitory molecules on CD8+ T cells are imperative to T-cell signaling and immune homeostasis. However, elevated expression of these molecules is correlated with dampened antitumor effector response as well as poorer patient survival. FcγRIIB is an inhibitory Fc receptor recently discovered on a subset of CD8+ T cells. FcγRIIB+ CD8+ T cells exhibit increased expression of activation markers, higher proliferative ability, and secrete more proinflammatory cytokines than their FcγRIIB- counterparts in mice and humans, making them imperative to the antitumor response. Recently, we discovered that an immunosuppressive cytokine, fibrinogen-like protein 2 (Fgl2), is a ligand that binds FcγRIIB on CD8+ T cells and induces FcγRIIB- mediated apoptosis of CD8+ T cells. The goal of this research is to interrogate the mechanism by which Fgl2 regulates tumor-specific FcγRIIB+ CD8+ T cells using syngeneic mouse models via the following aim. AIM 1 (F99): Determine the cellular and molecular mechanism by which Fgl2 critically regulates tumor-specific CD8+ T cells. Our studies show that both Foxp3+ regulatory T cells and CD8+ T cells express Fgl2 at the tumors of mice and humans. Thus, we will determine if Fgl2 secreted by these cell types is necessary and/or sufficient for FcγRIIB-mediated CD8+ T-cell apoptosis, findings which would provide the impetus for subsequent therapeutic targeting of this cell type. Additionally, as we have discovered that FcγRIIB-Fgl2 binding induces apoptosis, the upstream requirements of apoptosis (e.g. T-cell receptor stimulation, proteins recruited to the intracellular domain of FcγRIIB) are proximal items of investigation in the latter part of Aim 1. Piecing together the pathway by which FcγRIIB induces apoptosis via Fgl2 could uncover a new CD8+ T cell pathway readily harnessed for future immunotherapies. AIM 2 (K00): Identify novel mechanisms of T cell resistance to cancer immunotherapy. After the F99 stage, I intend to transition to the K00 stage to begin postdoctoral studies. Numerous studies highlight the role of elevated checkpoint molecule expression (PD-1, TIM-3) as well as decreased proinflammatory cytokine production (IFNγ, TNF) in mediating resistance to ICB. The current paradigm in cancer immunotherapy revolves around the suppressive impact of the tumor microenvironment on T cells, but the existence and impact of immunosuppressive factors secreted by effector CD8+ T cells themselves is incompletely understood. The impact of the proposed aims is considerable as they will identify novel targets, that could rescue a population of memory CD8+ T cells that are crucial to the immune response to tumor.

项目概要五十分之一的美国人在其一生中将被诊断出患有黑色素瘤，而皮肤黑色素瘤是最常见的黑色素瘤。最致命的皮肤癌免疫疗法是治疗这种疾病和细胞毒性的突破性方法。 CD8+ T 细胞肿瘤浸润是免疫治疗成功的关键因素，因此，确定有效的治疗方法。提高患者肿瘤特异性 CD8+ T 细胞反应的强度和功能的策略 CD8+ T 细胞上的抑制分子对于 T 细胞信号传导和免疫至关重要。然而，这些分子的表达升高与抗肿瘤效应物的减弱相关。 FcγRIIB 是最近在一个子集上发现的抑制性 Fc 受体。 CD8+ T 细胞的 FcγRIIB+ CD8+ T 细胞表现出活化标记物表达增加、增殖能力增强。能力，并在小鼠和人类中分泌比 FcγRIIB-抗体更多的促炎细胞因子，最近，我们发现了一种免疫抑制药物。细胞因子，纤维蛋白原样蛋白 2 (Fgl2)，是一种配体，可结合 CD8+ T 细胞上的 FcγRIIB，并诱导 FcγRIIB- 本研究的目的是探究 Fgl2 介导的 CD8+ T 细胞凋亡的机制。使用同基因小鼠模型通过以下 AIM 1 调节肿瘤特异性 FcγRIIB+ CD8+ T 细胞。 (F99)：确定 Fgl2 关键调节肿瘤特异性的细胞和分子机制我们的研究表明，Foxp3+ 调节性 T 细胞和 CD8+ T 细胞在肿瘤中均表达 Fgl2。因此，我们将确定这些细胞类型分泌的 Fgl2 是否是必要的和/或足够的。对于 FcγRIIB 介导的 CD8+ T 细胞凋亡，这些发现将为后续研究提供动力此外，我们发现 FcγRIIB-Fgl2 结合诱导这种细胞类型的治疗靶向。细胞凋亡，细胞凋亡的上游要求（例如 T 细胞受体刺激、招募至细胞的蛋白质） FcγRIIB 的胞内结构域）是目标 1 部分中最接近的研究项目。拼凑在一起 FcγRIIB 通过 Fgl2 诱导细胞凋亡的途径可以很容易地发现新的 CD8+ T 细胞途径用于未来的免疫疗法 AIM 2 (K00)：确定 T 细胞耐药的新机制。癌症免疫治疗。在F99阶段之后，我打算过渡到K00阶段，开始博士后研究。许多研究强调了检查点分子表达升高（PD-1、TIM-3）以及减少促炎细胞因子（IFNγ、TNF）的产生，介导 ICB 耐药。癌症免疫治疗的范例围绕肿瘤微环境的抑制影响 T细胞，但效应CD8+T细胞本身分泌的免疫抑制因子的存在及影响所提出的目标的影响是相当大的，因为它们将确定新的目标，这可以拯救对肿瘤免疫反应至关重要的记忆 CD8+ T 细胞群。