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.

项目摘要/摘要肿瘤可以利用正常生理免疫调节的机制来抑制肿瘤特异性免疫反应。针对免疫检查点的靶向免疫疗法，例如PD-1/PD-L1和 CTLA4，有改善的患者预后，但仅在一部分癌症中有效。耐用的响应在某些因检查点靶向疗法引起的患者中，人们对识别和针对其他先天和适应性免疫检查点。最近的研究已将受体酪氨酸激酶的Tyro3/axl/mer（TAM）家族鉴定为一种新颖先天免疫检查站。 Ubil等。（JCI，2018年）表明肿瘤分泌Pros1，tyro3/mer配体，抑制宿主巨噬细胞的促炎M1反应。 PROS1约束诱导 p38和ptp1b到MER，防止p38的核易位以及随后的M1相关表达基因。巨噬细胞MER或PTP1B的遗传缺失可在Pros1存在下恢复M1极化。通过靶向ProS1：巨噬细胞MER信号传导可能可以增强癌症免疫疗法。更好地理解和防止MER介导的免疫抑制以下特定提出了目的：1）确定Mer激酶活性和衔接蛋白在M1中的作用抑制，2）确定通过Pros1分泌肿瘤的可变免疫抑制的基础，3）确定 PTP1b抑制作用是否可以增加肿瘤内免疫浸润和改善生存。为了确定MER激酶活性的重要性，CRISPR将用于遗传消融MER ATP 在PROS1诱导的M1抑制过程中，用于监测全局转录变化的结合位点和RNASEQ。生物信息学分析将确定受MER激酶影响的关键途径，该途径将在生化上得到验证。免疫沉淀和蛋白质组学分析将用于确定Pros1诱导的重要性动态衔接蛋白募集和新蛋白质：蛋白质关联。微妙的遗传改变会导致降低Pros1蛋白活性。肿瘤ProS1序列的变化将与抑制能力相关 M1极化和构建的预测模型，以确定哪些肿瘤将容易受到PROS1：MER的影响靶向疗法。药理学PTP1B抑制（单和联合疗法）的功效增加肿瘤免疫浸润和存活率将在原发性和转移性肿瘤模型中确定。拟议的研究共同确定了新的治疗靶标，以防止Pros1：MER介导免疫抑制，关于哪些患者可能受益于PROS1：MER靶向治疗的产量预测标准以及药理学PTP1B抑制是否是改善对癌症免疫反应的可行策略。