An innate immune checkpoint in cancer immunotherapy

癌症免疫治疗中的先天免疫检查点

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos 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

项目摘要

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.

我们的应用程序是一个试点项目，重点是通过以下方式消除癌症治疗的意外副作用揭示处于临床和临床前开发阶段的新型免疫疗法的健康风险。受体酪氨酸激酶 (RTK) 基因 Tyro3、Axl 和 Mertk 是新近鉴定的旁系同源基因作为“先天免疫检查点”，此类 RTK 的阻断正在作为免疫疗法进行开发。然而，我们在这里提供一些旁系同源物的初步数据。在大脑中的星形胶质细胞和小胶质细胞中表达，对于维持具体来说，星形胶质细胞中 Mertk 和 Axl 功能的丧失不会影响大脑健康和神经认知功能。影响出生后早期大脑发育（P45），但星形胶质细胞在小鼠 3 个月大时，这些星形胶质细胞在 9 个月大时发生自发激活。随着年龄的增长，我们观察到脂褐素在大脑中的积累，尽管在学习和记忆任务中表现良好。 3 个月和 6 个月大时正常，9 个月大的小鼠表现出海马依赖性缺陷此外，我们还观察到阿尔茨海默病患者小胶质细胞中 Axl 的消融。疾病（AD）小鼠模型（5xFAD 小鼠）加速了这些小鼠的学习和记忆缺陷。关于大脑中 AXL 和 MERTK 功能需求的新知识，我们认为有必要全面调查针对这些 RTK 的激酶活性是否会对神经认知产生不良影响。激酶主要通过其酶活性来磷酸化底物，我们选择采取因此，我们的应用还包括开发一种新资源——AXL激酶——。我们的实验室已经提供了 MertkKD 小鼠模型。我们还将研究靶向激酶功能对大脑稳态以及学习和记忆的影响。在 AD 小鼠模型中研究 AXL 功能值得注意的是，我们的方法本质上是相同的。与用于生成初步数据的方法相同。初步数据将在 MertkKD 和/或 AxlKD 小鼠上进行，我们将在不同年龄进行测定。描述了大脑中观察到的表型的年龄依赖性发作。 MertkKD 和/或 AxlKD 小鼠以及动物的行为变化不仅将提供一种新的了解 MERTK 和 AXL 激酶在大脑健康和神经认知功能中的作用，同时也将提供基于 AXL 和/或 MERTK 的肿瘤免疫疗法的脑排除疗法的基本原理。激酶的独立于激酶的支架功能也已被描述存在，这将在以下方面进行研究。如果我们的研究未能揭示 Axl 基因敲除或 Axl 基因敲除观察到的表型，那么未来默特克。

项目成果

期刊论文数量（22）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

凝血病和炎症性疾病：“蛇鲨的一瞥”。

DOI：
发表时间：
2018
期刊：
影响因子：
7
作者：
Del Carmen, Silvina;Hapak, Sophie M;Ghosh, Sourav;Rothlin, Carla V
通讯作者：
Rothlin, Carla V

Lifting the innate immune barriers to antitumor immunity.

解除抗肿瘤免疫的先天免疫障碍。

DOI：
发表时间：
2020
期刊：
影响因子：
0
作者：
Rothlin, Carla V;Ghosh, Sourav
通讯作者：
Ghosh, Sourav

Polyanionic carbosilane dendrimers against viral infections: Human immunodeficiency Virus Type 1, Herpes Simplex Type 2 and Respiratory Syncytial Virus

聚阴离子碳硅烷树状聚合物可抵抗病毒感染：人类免疫缺陷病毒 1 型、单纯疱疹病毒 2 型和呼吸道合胞病毒

DOI：
发表时间：
2017-12-14
期刊：
影响因子：
0
作者：
R. Diez
通讯作者：
R. Diez

Antiphospholipid Antibodies Inhibit Trophoblast Toll-Like Receptor and Inflammasome Negative Regulators.

抗磷脂抗体抑制滋养层 Toll 样受体和炎性小体负调节因子。

DOI：
发表时间：
2018
期刊：
影响因子：
0
作者：
Mulla, Melissa J;Weel, Ingrid C;Potter, Julie A;Gysler, Stefan M;Salmon, Jane E;Peraçoli, Maria T S;Rothlin, Carla V;Chamley, Lawrence W;Abrahams, Vikki M
通讯作者：
Abrahams, Vikki M

Funerals and Feasts: The Immunological Rites of Cell Death

葬礼和宴会：细胞死亡的免疫仪式