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

询问 CD8 T 细胞上的 Fgl2-FcγRIIB 轴：介导肿瘤特异性记忆 CD8 T 细胞凋亡的新机制

• 批准号: 10605856
• 负责人: Kelsey Bennion
• 金额: $ 2.73万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2023-08-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10605856
• 关键词: Address; American; Antigens; Antitumor Response; Apoptosis; B-Lymphocytes; Binding; CASP3 gene; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Patient; Cell Survival; Cell secretion; Cells; Characteristics; Cutaneous Melanoma; Cytoplasmic Tail; Data; Development; Diagnosis; Disease; Event; Exhibits; FOXP3 gene; Fc Receptor; Fibrinogen; Flow Cytometry; Gene set enrichment analysis; Genes; Genetic; Goals; Hematopoietic; Homeostasis; Human; Immune; Immune response; Immunity; Immunoglobulin G; Immunologics; Immunotherapeutic agent; Immunotherapy; In Vitro; In complete remission; Induction of Apoptosis; Infiltration; Inflammatory; Investigation; Knock-out; Knockout Mice; Label; Ligand Binding; Ligands; Malignant Neoplasms; Mediating; Melanoma Cell; Memory; Modeling; Molecular; Mus; Myeloid Cells; Pathway interactions; Patients; Phenotype; Phosphoric Monoester Hydrolases; Population; Protein Isoforms; Proteins; Proteomics; Publications; Qualifying; RNA; Regulation; Regulatory T-Lymphocyte; Research; Role; Signal Pathway; Signal Transduction; Skin; Skin Cancer; Source; Surface; T cell infiltration; T cell response; T-Lymphocyte; Therapeutic; Transcript; Transgenic Organisms; Tumor Immunity; autocrine; cancer immunotherapy; cancer infiltrating T cells; cell type; cytokine; cytotoxic; cytotoxic CD8 T cells; exhaust; fighting; improved; insight; melanoma; mouse model; neoplasm immunotherapy; novel; patient response; prevent; programmed cell death protein 1; receptor; recruit; response; success; therapeutic target; transcriptome sequencing; transcriptomics; tumor

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 aims. AIM 1: Determine the cellular source of Fgl2 that 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. AIM 2: Elucidate the mechanism by which the CD8+ T-cell isoform of FcγRIIB induces apoptosis upon ligand binding by Fgl2. Our studies show that CD8+ T cells express a distinct isoform of FcγRIIB that can be bound by Fgl2, but the immediate signaling events after Fgl2-FcγRIIB binding remain unknown. We will identify proteins associated with the intracellular domain of FcγRIIB, specifically after ligand binding by Fgl2. This project is in the context of melanoma as therapeutic success is heavily influenced by CD8+ T-cell infiltration, but the impact of these findings could be applied to other immunologically “hot” tumors where immunotherapies are gaining momentum. Our possession of several mouse models and unique expertise on the role of FcγRIIB in CD8+ T-cell responses uniquely qualify us to address the proposed aims. The impact of the proposed aims is considerable as they will identify novel targets, that when blocked, could rescue a population of memory CD8+ T cells that are crucial to the immune response to tumor. Then, these “rescued” cells would unleash their effector function to improve melanoma patient response. As CD8+ T-cell inhibitory molecules and immunosuppressive cytokines negatively impact CD8+ T-cell infiltration, studying these interactions are of paramount importance as we enter an era of cancer immunotherapy- a treatment dependent on the patient CD8+ T-cell response.

项目概要： 五十分之一的美国人将在他们的一生中被诊断出患有黑色素瘤，皮肤黑色素瘤是最常见的黑色素瘤。 最致命的皮肤癌癌症免疫疗法是治疗这种疾病和细胞毒性的突破性方法 CD 8 + T细胞肿瘤浸润是免疫成功的关键因素。因此，确定有效的 增加患者肿瘤特异性CD 8 + T细胞应答的幅度和功能的策略 仍然是一个重要的目标。CD 8 + T细胞上的抑制分子对于T细胞信号传导和免疫应答是必要的。 体内平衡然而，这些分子的表达升高与抑制的抗肿瘤效应相关， 反应以及较差的患者存活率。FcγRIIB是最近在一个亚群上发现的抑制性Fc受体 CD 8 + T细胞FcγRIIB+ CD 8 + T细胞表现出活化标志物表达增加，增殖性增加， 在小鼠和人类中，与FcγRIIB-对应物相比， 使得它们对于抗肿瘤反应是必要的。最近，我们发现一种免疫抑制剂 细胞因子纤维蛋白原样蛋白2（Fgl 2）是一种配体，可结合CD 8 + T细胞上的FcγRIIB，并诱导FcγRIIB-1表达。 介导的CD 8 + T细胞凋亡。本研究的目的是探讨Fgl 2 通过以下目的使用同基因小鼠模型调节肿瘤特异性FcγRIIB+ CD 8 + T细胞。目标1： 确定关键调节肿瘤特异性CD 8 + T细胞的Fgl 2的细胞来源。我们的研究 显示Foxp 3+调节性T细胞和CD 8 + T细胞均在小鼠和人的肿瘤处表达Fgl 2。因此，在本发明中， 我们将确定这些细胞类型分泌的Fgl 2是否是Fcγ RIIB介导的CD 8 + T细胞增殖所必需和/或足够的。 T细胞凋亡，这一发现将为随后针对该细胞类型的治疗提供动力。 目的2：阐明FcγRIIB的CD 8 + T细胞亚型诱导细胞凋亡的机制， 通过Fgl 2的配体结合。我们的研究表明，CD 8 + T细胞表达不同的FcγRIIB亚型， Fgl 2-FcγRIIB结合后的直接信号传导事件仍然未知。我们将确定 与FcγRIIB的胞内结构域相关的蛋白质，特别是在Fgl 2结合配体后。这个项目 是在黑色素瘤的背景下，因为治疗成功受到CD 8 + T细胞浸润的严重影响，但 这些发现的影响可以应用于其他免疫学上的“热”肿瘤， 势头越来越猛我们拥有几种小鼠模型和关于FcγRIIB在 CD 8 + T细胞反应使我们有独特的资格来实现所提出的目标。拟议目标的影响是 相当可观，因为他们将确定新的目标，当阻断时，可以拯救记忆CD 8 + T细胞的群体。 对肿瘤免疫反应至关重要的细胞。然后，这些“获救”的细胞会释放出它们的效应子， 功能，以改善黑素瘤患者的反应。作为CD 8 + T细胞抑制分子和免疫抑制分子， 细胞因子对CD 8 + T细胞浸润产生负面影响，研究这些相互作用至关重要， 我们进入了一个癌症免疫治疗的时代-一种依赖于患者CD 8 + T细胞反应的治疗。