MerTK and the Innate Immune Response to Melanoma

MerTK 和对黑色素瘤的先天免疫反应

• 批准号: 9231607
• 负责人: H. Shelton Earp
• 金额: $ 34.77万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9231607
• 关键词: Antibodies; Antigens; Apoptosis; Apoptotic; Autoantigens; Autoimmunity; Binding; Blood Platelets; CTLA4 gene; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Combined Modality Therapy; Complex; Cross Presentation; Data; Dendritic Cells; Detection; Eragrostis; Family; Flow Cytometry; Fostering; Genes; Genetic; Genetic Engineering; Genetically Engineered Mouse; Human; Hypoxia; Immune; Immune checkpoint inhibitor; Immune response; Immunization; Immunohistochemistry; Immunosuppression; Immunosuppressive Agents; Individual; Inflammatory; Inflammatory Response Pathway; Ingestion; Innate Immune Response; Interleukin-10; Interleukin-12; Knock-out; Knockout Mice; Ligands; Location; Malignant Neoplasms; Mediating; Metastatic Melanoma; Methods; Modeling; Mus; Myelogenous; Natural Killer Cells; Neoplasm Metastasis; Organism; Orphan; Outcome; Ovum; Patients; Phenotype; Prevalence; Protein S; Receptor Protein-Tyrosine Kinases; Regulatory T-Lymphocyte; Research Design; Role; Serine; Signal Transduction; Suppressor-Effector T-Lymphocytes; Surface; T cell response; T-Lymphocyte; Testing; Therapeutic; Tissues; Transforming Growth Factor beta; Treatment Efficacy; Tumor Immunity; Tyrosine Kinase Inhibitor; Wound Healing; autocrine; cell growth; cell motility; cell type; checkpoint therapy; cytokine; exosome; immune checkpoint; immune function; inhibitor/antagonist; insight; kinase inhibitor; link protein; macrophage; melanoma; member; monocyte; neoplastic; neoplastic cell; overexpression; paracrine; pre-clinical; prevent; receptor; response; small molecule; study characteristics; targeted agent; therapeutic evaluation; therapeutic target; tumor; tumor growth; tumor microenvironment

The TAM family (Tyro3, Axl and MerTK) of receptor tyrosine kinases (RTKs) was one of the last families identified and one of the last to evolve. Their principal role in multicellular organisms appears to be detection of phosphatidyl serine (PtdSer) through a linking protein ligand (e.g. Gas6 or ProS) that together bind to and activate MerTK and intracellular signaling. PtdSer is exposed on the surface of aggregating platelets, exosomes and most prominently on the external surface of billions of cells that daily undergo apoptosis. The best studied homeostatic function of the family is the macrophage role of MerTK as it responds to apoptotic PtdSer by triggering ingestion (effercytosis) and signaling that this is “self-material”. This signal prevents an inflammatory macrophage response (e.g. IL-12) and polarizes the macrophage to an M2-like (e.g. IL-10, TGFb), wound healing, alternatively activated phenotype. This MerTK action is crucial for preventing autoimmunity efficiently ingesting dying cells and clearing self-antigens; this MerTK action is deleterious and immunosuppressive in tumor microenvironment (TME) and its innate immune infiltrate. TME immunosuppressive activities are stimulated by MerTK alone or in combination with Axl and Tyro 3 signaling in the innate immune cell repertoire. For example, our new data shows that all three TAM RTKs are present in Myeloid Derived Suppressor Cells and each (MerTK, Axl and Tyro 3) enhances MDSC suppressive action. MerTK activation also is key in the suppression of cross presentation by the tolerizing dendritic cell in which MerTK is substantially upregulated. In metastatic melanoma, immune checkpoint therapy has produced remarkable responses, some of which are durable. However, patients without an M1, Th1 immune infiltrate are less likely to benefit. Our overall hypothesis is that MerTK, Axl and Tyro 3 are in part responsible for the counterproductive, immunosuppressive immune infiltrate in melanoma (and other tumor types) through their innate immune cell action. This TAM RTK immunosuppressive action is probably present in most TMEs which are characterized by hypoxia, abundant apoptotic cells, and presence of secreted paracrine and autocrine TAM ligands (Gas6 and ProS). Our objective is to characterize the MerTK (and Axl, Tyro 3) signals in MDSCs, macrophages monocytes and tolerizing DCs, their downstream mechanisms and their consequences for the adaptive T reg and T eff cell responses. We will use wild type and knockout mice with preclinical syngeneic and genetically-engineered mouse melanomas as our models. We have UNC synthesized small molecule MerTK (and newer UNC TAM RTK) inhibitors as well as genetic methods to determine if inhibition of MerTK and other TAM receptors can produce an immune-modulatory tumor response. We will also test whether the combinations of immune checkpoint antibodies (anti-CTLA4 and anti-PD-1) and TAM RTK inhibitors will increase therapeutic efficacy.

受体酪氨酸激酶 (RTK) 的 TAM 家族（Tyro3、Axl 和 MerTK）是最后的家族之一 它们在多细胞生物中的主要作用似乎是检测。 磷脂酰丝氨酸 (PtdSer) 通过连接蛋白配体（例如 Gas6 或 ProS）共同结合和 激活 MerTK 和细胞内信号传导，PtdSer 暴露在聚集的血小板表面， 外泌体，最显着的是每天经历凋亡的数十亿个细胞的外表面。 该家族的稳态功能研究最多的是 MerTK 在响应细胞凋亡时的巨噬细胞作用 PtdSer 通过触发摄取（胞吞作用）并发出信号表明这是“自身物质”。 炎症巨噬细胞反应（例如 IL-12）并将巨噬细胞极化为 M2 样细胞（例如 IL-10、 TGFb）、伤口愈合、替代性激活表型 这种 MerTK 作用对于预防至关重要。 自身免疫有效地吞噬垂死细胞并清除自身抗原；这种 MerTK 作用是有害的并且 肿瘤微环境（TME）中的免疫抑制及其先天免疫浸润。 单独使用 MerTK 或与 Axl 和 Tyro 3 信号联合使用可刺激免疫抑制活性 例如，我们的新数据显示所有三种 TAM RTK 都存在于先天免疫细胞库中。 骨髓源性抑制细胞（MerTK、Axl 和 Tyro 3）均增强 MDSC 抑制作用。 MerTK 激活也是抑制耐受树突状细胞交叉呈递的关键，其中 MerTK 大幅上调。 在转移性黑色素瘤中，免疫检查点疗法产生了显着的反应，其中一些是 然而，没有 M1、Th1 免疫浸润的患者总体受益的可能性较小。 假设 MerTK、Axl 和 Tyro 3 部分负责适得其反的免疫抑制 TAM RTK 通过其先天免疫细胞作用对黑色素瘤（和其他肿瘤类型）进行免疫浸润。 免疫抑制作用可能存在于大多数 TME 中，其特点是缺氧、丰富 凋亡细胞，以及分泌的旁分泌和自分泌 TAM 配体（Gas6 和 ProS）的存在。 目的是表征 MDSC、巨噬细胞、单核细胞和 耐受 DC、其下游机制及其对适应性 T reg 和 T eff 细胞的影响 我们将使用临床前同基因和基因工程的野生型和基因敲除小鼠。 我们有 UNC 合成的小分子 MerTK（以及更新的 UNC TAM）作为我们的模型。 RTK）抑制剂以及确定 MerTK 和其他 TAM 受体抑制是否可以的遗传方法 我们还将测试免疫组合是否会产生免疫调节肿瘤反应。 检查点抗体（抗CTLA4和抗PD-1）和TAM RTK抑制剂将提高治疗效果。