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目标调节肿瘤特异性 FcγRIIB+ CD8+ T 细胞： 确定关键调节肿瘤特异性 CD8+ T 细胞的 Fgl2 的细胞来源。 显示 Foxp3+ 调节性 T 细胞和 CD8+ T 细胞在小鼠和人类的肿瘤中表达 Fgl2。 我们将确定这些细胞类型分泌的 Fgl2 对于 FcγRIIB 介导的 CD8+ 是否是必要和/或充分的 T 细胞凋亡，这一发现将为后续针对该细胞类型的治疗靶向提供动力。 目标 2：阐明 FcγRIIB 的 CD8+ T 细胞亚型诱导细胞凋亡的机制 我们的研究表明，CD8+ T 细胞表达一种独特的 FcγRIIB 亚型，可以通过 Fgl2 与配体结合。 被 Fgl2 结合，但 Fgl2-FcγRIIB 结合后的直接信号事件仍然未知。 与 FcγRIIB 胞内结构域相关的蛋白质，特别是在 Fgl2 配体结合后。 是在黑色素瘤的背景下，因为治疗成功很大程度上受到 CD8+ T 细胞浸润的影响，但 这些发现的影响可以应用于其他免疫“热”肿瘤，其中免疫疗法是有效的 我们拥有多种小鼠模型以及关于 FcγRIIB 在其中的作用的独特专业知识。 CD8+ T 细胞反应使我们有资格实现拟议目标。拟议目标的影响是。 相当重要，因为他们将识别新的目标，当这些目标被阻断时，可以拯救一群记忆 CD8+ T 然后，这些“被拯救”的细胞将释放它们的效应子。 作为 CD8+ T 细胞抑制分子和免疫抑制分子，具有改善黑色素瘤患者反应的功能。 细胞因子对 CD8+ T 细胞浸润产生负面影响，研究这些相互作用至关重要，因为 我们进入了癌症免疫疗法的时代——一种依赖于患者 CD8+ T 细胞反应的治疗方法。