Enhanced Immunotherapy by Targeting the Pros1:Macrophage Mer Axis

通过靶向 Pros1：巨噬细胞 Mer 轴增强免疫治疗

基本信息

批准号：
10304878
负责人：
Eric S Ubil
金额：
$ 19.24万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-09 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10304878
关键词：
Adaptor Signaling Protein Affect Binding Binding Sites Biochemical Bioinformatics CTLA4 gene Cancer Model Cells Clinical Clinical Treatment Clustered Regularly Interspaced Short Palindromic Repeats Coculture Techniques Combined Modality Therapy Complex Data Environment Excision Family Gene Expression Genes Genetic Genetic Transcription Genetic Variation Genomics Human Immune Immune Targeting Immune response Immunoprecipitation Immunosuppression Immunotherapy Inflammatory Inflammatory Response Lead Ligands Macrophage Activation Malignant Neoplasms Mediating Modeling Monitor Mus Mutation Myeloid Cells Neoplasm Metastasis Nuclear Translocation Operative Surgical Procedures Outcome PD-1/PD-L1 Pathway interactions Patient-Focused Outcomes Patients Pharmacology Phenotype Phosphotransferases Physiological Predisposition Primary Neoplasm Proteins Proteomics Receptor Protein-Tyrosine Kinases Receptor Signaling Role Signal Transduction System The Cancer Genome Atlas Tumor Cell Line Tumor-Derived Tumor-infiltrating immune cells Variant adaptive immune response cancer immunotherapy clinical development clinically relevant cooking immune activation immune checkpoint immunoregulation improved in vivo inhibitor innate immune checkpoint insight interest kinase inhibitor macrophage neoplastic cell new therapeutic target novel novel therapeutics p38 Mitogen Activated Protein Kinase predictive modeling prevent receptor recruit response targeted treatment therapy outcome transcriptome sequencing tumor tumor progression

项目摘要

PROJECT SUMMARY/ABSTRACT Tumors can utilize mechanisms of normal physiological immune regulation to suppress the tumor-specific immune response. Targeted immunotherapies directed against immune checkpoints, like PD-1/PD-L1 and CTLA4, have improved patient outcomes but are only effective in a subset of cancers. The durable responses of some patients, resulting from checkpoint-targeted therapy, has sparked great interest in identifying and targeting other innate and adaptive immune checkpoints. Recent studies have identified the Tyro3/Axl/Mer (TAM) family of receptor tyrosine kinases as a novel innate immune checkpoint. Ubil et al. (JCI, 2018) show that tumors secrete Pros1, a Tyro3/Mer ligand, which suppresses the pro-inflammatory M1 response of host macrophages. Pros1 binding induces the recruitment of p38 and PTP1b to Mer, preventing nuclear translocation of p38 and subsequent expression of M1 associated genes. Genetic deletion of macrophage Mer or PTP1b restores M1 polarization in the presence of Pros1. By targeting Pros1:macrophage Mer signaling it may be possible to enhance cancer immunotherapy. To better understand and prevent Mer mediated immune suppression the following specific aims are proposed: 1) Determine the roles of Mer kinase activity and adapter protein recruitment in M1 suppression, 2) Identify the basis for variable immune suppression by Pros1 secreting tumors and 3) Ascertain whether PTP1b inhibition as mono- or combination therapy can increase intra-tumoral immune infiltrate and improve survival. To establish the importance of Mer kinase activity, CRISPR will be used to genetically ablate the Mer ATP binding site and RNAseq used to monitor global transcriptional changes during Pros1 induced M1 suppression. Bioinformatics analysis will identify key pathways affected by Mer kinase, which will be validated biochemically. Immunoprecipitation and proteomic analysis will be used to determine the importance of Pros1-induced dynamic adapter protein recruitment and novel protein:protein associations. Subtle genetic alterations can lead to reduced Pros1 protein activity. Changes in tumor Pros1 sequence will be correlated with ability to suppress M1 polarization and a predictive model constructed to identify which tumors will be susceptible to Pros1:Mer targeted therapy. Efficacy of pharmacological PTP1b inhibition (mono- and combination therapy) to increase tumor immune infiltrate and survival will be determined in primary and metastatic tumor models. Together, the proposed study may identify novel therapeutic targets to prevent Pros1:Mer mediated immune suppression, yield predictive criteria as to which patients may benefit from Pros1:Mer targeted therapy and whether pharmacological PTP1b inhibition is a viable strategy to improve the immune response to cancer.

项目概要/摘要肿瘤可以利用正常的生理免疫调节机制来抑制肿瘤特异性的免疫反应。免疫反应。针对免疫检查点的靶向免疫疗法，如 PD-1/PD-L1 和 CTLA4 改善了患者的治疗效果，但仅对一部分癌症有效。持久的反应一些患者因检查点靶向治疗而产生的症状，引起了人们对识别和治疗的极大兴趣。针对其他先天性和适应性免疫检查点。最近的研究发现 Tyro3/Axl/Mer (TAM) 受体酪氨酸激酶家族是一种新型的受体酪氨酸激酶家族。先天免疫检查点。乌比尔等人。（JCI，2018）表明肿瘤分泌 Pros1，一种 Tyro3/Mer 配体，抑制宿主巨噬细胞的促炎 M1 反应。 Pros1 结合诱导招募 p38 和 PTP1b 转化为 Mer，防止 p38 的核转位以及随后相关的 M1 表达基因。在 Pros1 存在的情况下，巨噬细胞 Mer 或 PTP1b 的基因删除可恢复 M1 极化。通过靶向 Pros1：巨噬细胞 Mer 信号传导，可能会增强癌症免疫疗法。为了更好地了解和预防 Mer 介导的免疫抑制，以下具体内容提出的目标是：1) 确定 Mer 激酶活性和接头蛋白募集在 M1 中的作用抑制，2) 确定 Pros1 分泌肿瘤的可变免疫抑制的基础，以及 3) 确定 PTP1b 抑制作为单一疗法或联合疗法是否可以增加肿瘤内免疫浸润以及提高生存率。为了确定 Mer 激酶活性的重要性，将使用 CRISPR 从基因上消除 Mer ATP 结合位点和 RNAseq 用于监测 Pros1 诱导 M1 抑制期间的全局转录变化。生物信息学分析将确定受 Mer 激酶影响的关键途径，并进行生化验证。免疫沉淀和蛋白质组分析将用于确定 Pros1 诱导的重要性动态接头蛋白招募和新型蛋白质：蛋白质关联。微妙的基因改变可能导致降低 Pros1 蛋白活性。肿瘤 Pros1 序列的变化将与抑制能力相关 M1 极化和构建预测模型来识别哪些肿瘤对 Pros1:Mer 敏感靶向治疗。药理学 PTP1b 抑制（单一和联合治疗）的疗效增加肿瘤免疫浸润和存活将在原发性和转移性肿瘤模型中确定。总之，拟议的研究可能会确定新的治疗靶点来预防 Pros1:Mer 介导的免疫抑制，得出哪些患者可能受益于 Pros1:Mer 靶向治疗的预测标准以及药物 PTP1b 抑制是否是改善癌症免疫反应的可行策略。