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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：
9447148
负责人：
Sourav Ghosh
金额：
$ 46.82万
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 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9447148
关键词：
Ablation Acute Antigen Presentation Antitumor Response Apoptotic Breast Cancer Model Cancer Model Cell physiology Cells Colon Carcinoma Complement Data Defect Defense Mechanisms Dendritic Cells Dendritic cell activation Development Diagnosis Disabled Persons Disease Drug usage Excision FDA approved Failure Future Genetic Genetically Engineered Mouse Growth Human Immune Immune checkpoint inhibitor Immune response Immune signaling Immune system Immunotherapeutic agent Immunotherapy Individual Infiltration Innate Immune System Interferon Type I Interferons Knock-in Mouse Knock-out Knockout Mice Lead Lymphoma MC38 MERTK gene Malignant Neoplasms Measures Mediating Modeling Molecular Mus Names Natural Immunity Patients Phagocytosis Phosphorylation Phosphotransferases Process Protein Tyrosine Kinase Proteins Receptor Protein-Tyrosine Kinases Regulation Reporting Resistance Sampling Signal Pathway Signal Transduction Specimen Stains T cell response T-Cell Activation T-Lymphocyte Testing Therapeutic Uses Tumor Immunity Tumor-Infiltrating Lymphocytes Tumor-associated macrophages adaptive immunity anti-cancer anti-tumor immune response base beta catenin biomarker panel cancer cell cancer genetics cancer immunotherapy cancer prevention cancer therapy checkpoint therapy comparative efficacy fighting human disease immune checkpoint immune checkpoint blockade improved improved functioning inhibitor/antagonist loss of function macrophage melanoma molecular targeted therapies mortality mouse model neutralizing antibody novel patient subsets pre-clinical predictive marker response sensor small molecule targeted treatment tumor tumor growth weapons

项目摘要

Cancer immunotherapy attempts to boost the body’s own defense mechanism – the immune system – to kill cancer cells and defeat cancer. Immunotherapy with T cell checkpoint inhibitors is promising to revolutionize cancer therapy. However, a major limitation of these therapies is that they are effective in only a subset of patients. Recent evidence suggests that enhanced T cell infiltration in the tumor is a predictive marker of positive response to T cell checkpoint inhibitors. Thus, failure to respond to T cell checkpoint inhibitors may correspond to a defect in the ability of the innate immune system to effectively engage adaptive anti-tumor immune response. In mice, we have identified and disabled a novel immune checkpoint mechanism, a cellular protein named MERTK, that is found in innate immune cells – the body’s first line of immune defense. MERTK limits the extent to which innate immune cells can get activated, which in turn controls how much the overall immune response would be. We have also detected the presence of MERTK in tumor-associated innate immune cells in human samples. In mouse models of cancer, genetic ablation of Mertk results in dramatic prevention of cancer growth. We propose to (i) use mouse models of cancers to investigate the mechanism/s by which loss of MERTK function improves anti-tumor immunity, (ii) test if acute ablation of Mertk in established tumors and the inactivation of its kinase activity are sufficient to overcome the failure to trigger anti- tumor T cell responses and restrict tumor growth, and (iii) to investigate the association between MERTK activation and the resistance to T cell checkpoint inhibitors in patients. Through these studies, we will better understand how the immune system can fight cancer when the MERTK brake is removed, obtain proof-of- concept for therapeutic use of drugs that would inhibit MERTK, and develop a predictive biomarker panel for the identification of a subset of patients that are likely to respond to MERTK inhibitors. In summary, our proposed studies can potentially identify a novel target for cancer immunotherapy that by itself, or in combination with FDA-approved checkpoint inhibitors or molecular targeted therapies, could significantly increase the percentage of patients that show objective response to anti-cancer therapy.

癌症免疫疗法试图增强人体自身的防御机制-免疫系统-杀死癌细胞和战胜癌症。使用T细胞检查点抑制剂的免疫疗法有望彻底改变癌症治疗。然而，这些疗法的主要局限性在于它们仅在一部分患者中有效。患者最近的证据表明，肿瘤中增强的T细胞浸润是肿瘤发生的预测标志物。对T细胞检查点抑制剂有阳性反应。因此，对T细胞检查点抑制剂的应答失败可能对应于先天免疫系统有效参与适应性抗肿瘤治疗的能力的缺陷免疫反应在小鼠中，我们已经确定并禁用了一种新的免疫检查点机制，即细胞免疫检查点机制。这种蛋白质名为MERTK，存在于先天免疫细胞中，是人体免疫防御的第一道防线。MERTK 限制了先天免疫细胞被激活的程度，这反过来又控制了整体免疫细胞的数量。免疫反应是什么。我们还检测到MERTK在肿瘤相关先天性巨噬细胞中的存在。人体样本中的免疫细胞在小鼠癌症模型中，Mertk的基因切除导致了显着的预防癌症生长。我们建议（i）使用小鼠癌症模型来研究其机制， MERTK功能的丧失通过其改善抗肿瘤免疫，（ii）测试是否急性消融MERTK，建立的肿瘤和其激酶活性的失活足以克服触发抗肿瘤的失败，肿瘤T细胞应答并限制肿瘤生长，以及（iii）研究MERTK与肿瘤细胞增殖和肿瘤细胞增殖之间的关联。活化和患者对T细胞检查点抑制剂的抗性。通过这些研究，我们将更好地了解当MERTK制动器被移除时，免疫系统如何对抗癌症，治疗性使用药物的概念，将抑制MERTK，并开发一个预测性生物标志物面板，确定可能对MERTK抑制剂有应答的患者子集。总之，我们的提出的研究可以潜在地确定癌症免疫治疗的新靶点，与FDA批准的检查点抑制剂或分子靶向治疗联合使用，增加对抗癌治疗显示出客观反应的患者的百分比。