An innate immune checkpoint in cancer immunotherapy

癌症免疫治疗中的先天免疫检查点

• 批准号: 10286793
• 负责人: Sourav Ghosh
• 金额: $ 41.55万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10286793
• 关键词: Ablation; Acceleration; Adverse effects; Age; Age-Months; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Animals; Anxiety; Astrocytes; Autoantigens; Automobile Driving; Behavioral; Biological Assay; Brain; CTLA4 gene; Cells; Collaborations; Complement; Data; Defect; Dendritic Cells; Development; Disease; Electron Microscopy; Frequencies; Future; Gene Expression Profile; Generations; Genes; Genetic; Genetic Transcription; Health; Health protection; Hippocampus (Brain); Histologic; Homeostasis; Immune; Immune response; Immunotherapeutic agent; Immunotherapy; Impaired cognition; Impairment; Individual; Inflammation; Institutes; Israel; Knock-out; Knockout Mice; Knowledge; Laboratories; Learning; Light; Lipofuscin; MERTK gene; Maintenance; Malignant Neoplasms; Memory; Memory Loss; Memory impairment; Messenger RNA; Microglia; Modeling; Moods; Morphology; Mus; Natural Immunity; Nerve Degeneration; Neurocognitive; Neurocognitive Deficit; Parents; Performance; Phagocytes; Phagocytosis; Pharmacology; Phenocopy; Phenotype; Phosphotransferases; Photoreceptors; Pilot Projects; Proteins; Receptor Protein-Tyrosine Kinases; Resources; Risk; Role; Structure of retinal pigment epithelium; T cell response; T-Lymphocyte; TREM2 gene; TYRO3 gene; Testing; Therapeutic; Tissue-Specific Gene Expression; Transcript; Tumor-associated macrophages; Work; adaptive immune response; adaptive immunity; age related; anti-tumor immune response; axl receptor tyrosine kinase; base; behavior test; brain health; cancer immunotherapy; clinical development; conditional knockout; experimental study; immune checkpoint; immune checkpoint blockade; innate immune checkpoint; loss of function; macrophage; mouse model; neoplasm immunotherapy; novel; paralogous gene; pathogen; postnatal; preclinical development; programmed cell death protein 1; receptor function; response; scaffold; tool; tumor; tumor-immune system interactions

Our application is a pilot project focused on eliminating unexpected adverse effects of cancer therapeutics by uncovering health risk of a new class of immunotherapeutics that are in clinical and preclinical development. Receptor tyrosine kinase (RTK) genes Tyro3, Axl and Mertk are paralogs that have been newly characterized as “innate immune checkpoints”. The blockade of this class of RTKs is in development as immunotherapies that can boost anti-tumor immune response. However, here we provide preliminary data that some paralogs are expressed in astrocytes and microglia in the brain, and are functionally important for the maintenance of brain health and neurocognitive functions. Specifically, loss of function of Mertk and Axl in astrocytes did not affect early postnatal brain development (P45), but astrocytes expressed unfolded protein response-genes in mice by 3-months of age, concomitant with these astrocytes undergoing spontaneous activation. By 9-months of age, we observed lipofuscin accumulation in the brain. Although performance in learning and memory tasks was normal at 3- and 6-months of age, 9-month old mice displayed defects in hippocampus-dependent learning and memory. Furthermore, we also observed that ablation of Axl in microglia in an Alzheimer's Disease (AD) mouse model (5xFAD mouse) accelerated learning and memory defects in these mice. In light of this novel knowledge of the functional requirement AXL and MERTK in the brain, we believe it is imperative to fully investigate if targeting the kinase activity of these RTKs can have adverse neurocognitive effects. Since kinases primarily function through their enzymatic activity to phosphorylate substrates, we are choosing to take this approach first. Therefore, our application also includes the development of a new resource – AXL kinase- dead or AxlKD mouse. A MertkKD is already available in our laboratory. We will use these mouse models to investigate the effect of targeting kinase function in brain homeostasis, and learning and memory. We will also investigate AXL function in the context of an AD mouse model. Notably, our approach is essentially identical with the approach used to generate the preliminary data. The same set of experiments included in the preliminary data will be performed on MertkKD and/or AxlKD mice. We will perform the assays at various ages to characterize the age-dependent onset of the phenotypes. Observed histological changes in the brain in the MertkKD and/or AxlKD mice, along with behavioral changes in the animal, will not only provide a novel understanding of MERTK and AXL kinase in the brain health and neurocognitive function, but will also provide a rationale for developing brain-excluded therapeutics for AXL- and/or MERTK-based tumor immunotherapy. Kinase-independent, scaffold-functions of kinases have also been described to exist. This will be pursued in the future if our studies fail to reveal the phenotype observed with genetic knockout of Axl or that of Axl and Mertk.

我们的应用是一个试点项目，旨在消除通过 发现临床和临床前开发中的新型免疫治疗剂的健康风险。 受体酪氨酸激酶（RTK）基因TYRO3，AXL和MERTK是旁系同源物 作为“先天免疫切口点”。作为免疫疗法，这类RTK的封锁正在开发中 这可以增强抗肿瘤免疫反应。但是，在这里我们提供一些旁系同源的初步数据 在大脑中的星形胶质细胞和小胶质细胞中表达，在维持功能上很重要 大脑健康和神经认知功能。具体而言，星形胶质细胞中MERTK和AXL功能的丧失没有 影响早期出生后脑发育（P45），但星形胶质细胞表达了未折叠的蛋白质反应基因 小鼠到3个月的年龄，与这些星形胶质细胞同时激活。到9个月 年龄，我们观察到脂肪霉素在大脑中的积累。尽管学习和记忆任务的表现 在3个月和6个月的年龄处正常，9个月大的小鼠在海马依赖性的缺陷中显示出缺陷 学习和记忆。此外，我们还观察到小胶质细胞中AXL在阿尔茨海默氏症中的消融 这些小鼠的疾病（AD）小鼠模型（5XFAD小鼠）加速学习和记忆缺陷。鉴于 对大脑中功能需求AXL和MERTK的这种新知识，我们认为必须 充分研究这些RTK的激酶活性是否可能具有不良神经认知效应。自从 激酶通过其酶促活性来磷酸化底物的一级功能，我们选择服用 这种方法首先。因此，我们的应用程序还包括开发新资源-Axl激酶 - 死亡或AxlKD鼠标。我们的实验室已经有Mertkkd。我们将使用这些鼠标模型 研究靶向激酶功能在脑体内稳态以及学习和记忆中的影响。我们也会 在AD鼠标模型的上下文中研究AXL函数。值得注意的是，我们的方法本质上是相同的 用该方法用于生成初步数据。在 初步数据将在MERTKKD和/或AXLKD小鼠上执行。我们将在不同年龄进行测定 表征表型的年龄依赖性发作。观察到大脑的组织学变化 Mertkkd和/或AxlKD小鼠，以及动物的行为改变，不仅会提供一种新颖的 了解脑健康和神经认知功能中MERTK和AXL激酶，但也将提供 用于开发用于基于AXL-和/或MERTK的肿瘤免疫疗法的脑排除疗法的理由。 激酶非依赖性的，激酶的支架功能也已被描述为存在。这将在 未来，如果我们的研究未能揭示用AXL的遗传敲除或AXL和AXL和AXL和AXL的表型 Mertk。

项目成果

Chronicles of Cell Death Foretold: Specificities in the Mechanism of Disposal.

• DOI: 10.3389/fimmu.2017.01743
• 发表时间: 2017
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Hughes LD;Bosurgi L;Ghosh S;Rothlin CV
• 通讯作者: Rothlin CV

Determining the effector response to cell death.

• DOI: 10.1038/s41577-020-00456-0
• 发表时间: 2021-05
• 期刊: Nature reviews. Immunology
• 作者: Rothlin CV;Hille TD;Ghosh S
• 通讯作者: Ghosh S

When aging gets on the way of disposal: Senescent cell suppression of efferocytosis.

• DOI: 10.1083/jcb.202212023
• 发表时间: 2023-02-06
• 期刊: The Journal of cell biology

Coagulopathies and inflammatory diseases: '…glimpse of a Snark'.

凝血病和炎症性疾病：“蛇鲨的一瞥”。

• DOI: 10.1016/j.coi.2018.09.005
• 发表时间: 2018
• 期刊: Current opinion in immunology
• 影响因子: 7
• 作者: DelCarmen,Silvina;Hapak,SophieM;Ghosh,Sourav;Rothlin,CarlaV
• 通讯作者: Rothlin,CarlaV

Macrophage function in tissue repair and remodeling requires IL-4 or IL-13 with apoptotic cells.

• DOI: 10.1126/science.aai8132
• 发表时间: 2017-06-09
• 期刊: Science (New York, N.Y.)
• 作者: Bosurgi L;Cao YG;Cabeza-Cabrerizo M;Tucci A;Hughes LD;Kong Y;Weinstein JS;Licona-Limon P;Schmid ET;Pelorosso F;Gagliani N;Craft JE;Flavell RA;Ghosh S;Rothlin CV
• 通讯作者: Rothlin CV