Myeloid cell-derived Granzyme B as an inducible enhancer of cancer immunotherapy

骨髓细胞衍生的颗粒酶 B 作为癌症免疫治疗的诱导增强剂

• 批准号: 9884738
• 负责人: Jonathan P. Butchar
• 金额: $ 35.2万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-10 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9884738
• 关键词: Antibodies; Antibody Therapy; Antibody-Dependent Enhancement; B-Lymphocytes; Binding; Blood; CD8-Positive T-Lymphocytes; Cell Lineage; Cell Proliferation; Cell Survival; Cell-Mediated Cytolysis; Cells; Chronic Lymphocytic Leukemia; Clinical Trials; Cytotoxic T-Lymphocytes; Data; Disease; Effector Cell; Enhancers; Event; Future; Genetic Transcription; Goals; Granzyme; Human; IgG Receptors; Immune; Immunomodulators; Immunotherapy; Inflammasome; Inflammatory; Investigation; Knowledge; Lead; Ligands; Malignant Neoplasms; Mediating; Methods; Molecular; Monoclonal Antibodies; Monoclonal Antibody Therapy; Myeloid Cells; Natural Killer Cells; Nurses; Patients; Peptide Hydrolases; Peripheral Blood Mononuclear Cell; Phagocytes; Phagocytosis; Process; Production; Receptor Activation; Role; Sampling; Serine Protease; Signal Pathway; Signal Transduction; T-Lymphocyte; TLR4 gene; TLR8 gene; Therapeutic antibodies; Toll-like receptors; Treatment Efficacy; Work; antibody-dependent cell cytotoxicity; antitumor effect; base; cancer immunotherapy; cancer therapy; cytokine; cytotoxic; cytotoxicity; experimental study; improved; interest; macrophage; monocyte; mouse model; neoplastic cell; novel; perforin; perforin 1; receptor; receptor function; response; tumor

PROJECT SUMMARY Our broad, long term objective is to understand the molecular details of Fcγ receptor (FcγR) function, with the goal of improving monoclonal antibody therapy for cancer. The antitumor effects of antibody therapy are largely mediated by FcγR, which become clustered and activated upon binding to the Fc portion of antibodies. Monocytes and macrophages are essential for antibody therapy to be effective, and FcγR activation in these cells can lead to pleiotropic responses. These include phagocytosis, antibody-dependent cellular cytotoxicity (ADCC), production of inflammatory cytokines, or a combination of these. Amongst these activities, the mechanisms by which monocytes / macrophages carry out ADCC remain the least understood. We have recently found that FcγR clustering can induce Granzyme B production by human monocytes and that ligands for Toll-like receptors (TLR) 4 and 8 can significantly enhance this response, as well as induce Granzyme B themselves. Granzyme B is a serine protease expressed predominantly by natural killer (NK) cells and CD8+ T cells, and is required for their cytotoxic functions. Given the central role of Granzyme B in NK cell- mediated ADCC, our finding that monocytes can also produce Granzyme B is remarkable as it provides an as- yet undiscovered anti-tumor function of monoclonal antibodies. Most notably we have also found that nurse- like cells (NLCs) generated from CLL patient blood also produce Granzyme B following FcγR activation and TLR8 ligand treatment, and they can engage in Granzyme-dependent ADCC of CLL cells. This latter observation is of particular interest, as NLCs typically promote CLL-cell survival and proliferation. We therefore hypothesize that Granzyme B production by monocytes and NLCs represents a critical aspect of the effector response to antibody-coated target cells. We propose to explore the significance of these findings specifically related to CLL immunotherapy in the following 3 specific aims: 1) Elucidate the mechanisms of Granzyme B induction by FcγR in monocytes/macrophages and NLCs, 2) Determine the mechanism of augmentation of FcγR-induced Granzyme B production by immune modulators and 3) Analyze the expression and function of Granzyme B by monocytes and monocyte-lineage cells in patient samples and mouse models of CLL. Upon completion of this study we will have fully explored an entirely new mechanism of antibody-mediated destruction of tumors by monocytes/macrophages and NLCs. These mechanistic studies will significantly enhance our understanding of ADCC mediated by these cells, and will likely provide information that can lead to the further enhancement of antibody therapy.

项目概要 我们广泛的长期目标是了解 Fcγ 受体 (FcγR) 功能的分子细节， 目标是改善癌症的单克隆抗体治疗。抗体疗法的抗肿瘤作用 主要由 FcγR 介导，FcγR 在与 FcγR 的 Fc 部分结合后聚集并被激活 抗体。单核细胞和巨噬细胞对于抗体治疗有效至关重要，而 FcγR 这些细胞的激活可以导致多效性反应。这些包括吞噬作用、抗体依赖性 细胞毒性（ADCC）、炎性细胞因子的产生或这些的组合。其中 对于单核细胞/巨噬细胞执行 ADCC 的机制仍然了解最少。 我们最近发现 FcγR 簇可以诱导人单核细胞产生颗粒酶 B，并且 Toll 样受体 (TLR) 4 和 8 的配体可以显着增强这种反应，并诱导 颗粒酶 B 本身。粒酶 B 是一种丝氨酸蛋白酶，主要由自然杀伤 (NK) 细胞表达 和 CD8+ T 细胞，并且是其细胞毒功能所必需的。鉴于颗粒酶 B 在 NK 细胞中的核心作用 介导的 ADCC，我们发现单核细胞也能产生颗粒酶 B，这一发现是值得注意的，因为它提供了一种作为- 单克隆抗体的抗肿瘤功能尚未被发现。最值得注意的是，我们还发现护士- 从 CLL 患者血液中产生的样细胞 (NLC) 在 FcγR 激活后也会产生颗粒酶 B TLR8配体治疗，它们可以参与CLL细胞的粒酶依赖性ADCC。后者 观察特别令人感兴趣，因为 NLC 通常会促进 CLL 细胞的存活和增殖。我们因此 假设单核细胞和 NLC 产生的颗粒酶 B 代表了效应器的一个关键方面 对抗体包被的靶细胞的反应。我们建议专门探讨这些发现的意义 与 CLL 免疫治疗相关的 3 个具体目标： 1) 阐明 Granzyme B 的机制 单核细胞/巨噬细胞和 NLC 中 FcγR 的诱导，2) 确定增强的机制 FcγR 诱导免疫调节剂产生颗粒酶 B，3) 分析颗粒酶 B 的表达和功能 粒酶 B 由 CLL 患者样本和小鼠模型中的单核细胞和单核细胞谱系细胞产生。 这项研究完成后，我们将充分探索抗体介导的全新机制 单核细胞/巨噬细胞和 NLC 破坏肿瘤。这些机制研究将显着 增强我们对这些细胞介导的 ADCC 的理解，并可能提供可以导致 进一步加强抗体治疗。