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Myeloid cell-expressed PTPN22 and anti-tumor immunity

骨髓细胞表达的 PTPN22 与抗肿瘤免疫

基本信息

批准号：
10530032
负责人：
Santiago Acero Bedoya
金额：
$ 4.83万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10530032
关键词：
Antigens Autoimmune Autoimmune Diseases Autoimmunity Biological CD8-Positive T-Lymphocytes Cancer Model Candidate Disease Gene Cause of Death Cell Lineage Cell physiology Cells Clinical Data Databases Dendritic Cells Detection Engineering Faculty Funding Genes Genetic Polymorphism Goals HLA Antigens Heterogeneity Human Hyperactivity Immune Immune response Immune system Immunotherapeutic agent Immunotherapy Incidence Individual Infiltration Institution Integration Host Factors Investigation Knock-out Knockout Mice Lead Ligands Link Malignant Neoplasms Mus Mutation Myeloid Cells PTPN22 gene Patients Pharmacology Phase Phosphoric Monoester Hydrolases Process Recurrent disease Refractory Regulator Genes Reporting Research Research Project Grants Resistance Risk Role Shapes Signal Transduction Single Nucleotide Polymorphism Site Source T cell response T-Cell Activation T-Lymphocyte Testing Tumor Immunity Tumor Suppressor Proteins Tumor-infiltrating immune cells United States United States National Institutes of Health Variant Work cancer therapy cell type checkpoint therapy clinical efficacy conditional knockout experimental study genetic signature genetic variant immune activation immune checkpoint improved insight knowledge base loss of function macrophage member mouse model neoplasm immunotherapy new therapeutic target novel patient subsets programmed cell death ligand 1 programmed cell death protein 1 recruit resistance mechanism response skills tenure track tumor tumor immunology tumor microenvironment tumor progression

项目摘要

PROJECT SUMMARY Immunotherapies that block the checkpoint molecules programmed cell death 1 (PD-1) and its ligand PD-L1 have revolutionized cancer treatment; however, a significant number of patients display resistance to immunotherapy, either de novo or with disease relapse after initial response [1-3]. Immunotherapy-refractory cases have prompted insight into mechanisms of resistance, which should ultimately lead to new strategies to expand clinical efficacy. Primary resistance is linked to lack of immune cell infiltration within the tumor microenvironment (TME), an observation which has prompted deeper investigation into the tumor and host factors that regulate the degree of spontaneous T cell activation and infiltration into tumor sites. One relevant source of inter-patient heterogeneity is the variable presence of polymorphisms (SNPs) in immune-regulatory genes, many of which have been linked previously to the propensity towards autoimmunity. In the F99 phase of this proposed plan, I will evaluate the utility of targeting an autoimmune-associated gene to increase immunotherapy efficacy. A SNP in the tyrosine-protein phosphatase non-receptor type 22 (PTPN22) gene is attributed with the greatest risk for autoimmune disease outside mutations in the human leukocyte antigen locus [4-6]. PTPN22 negatively regulates the activation of multiple immune compartments, with loss-of-function variants leading to heightened immune cell activation in mice and humans [7-8]. This increase in immune activity is attributed to the expansion of activated CD8+ T cells, however, work reported to date have utilized global knockout mice (KO), confounding the specific role of PTPN22 in other cell lineages relevant for anti-tumor immunity, in particular myeloid cells. We thus developed a PTPN22fl/fl mouse to study its effect in different immune cell types via conditional KO mouse models. I hypothesize that loss of PTPN22 augments the ability of DCs to activate antigen specific CD8+ T cells through 1) improved priming in the tdLN or recruitment to and/or survival signaling in the TME and that 2) deletion of PTPN22 in macrophages also may potentiate anti-tumor immunity. In the K00 phase of the proposed plan, I aim to identify novel targets governing anti-tumor immunity and immunotherapy efficacy by 1) identifying autoimmune related SNPs whose loss of function variants correlate with increased tumor immune infiltration and 2) characterizing the effect of these targets on tumor progression and immunotherapy response through functional studies using conditional KO mice. This work holds the potential to elucidate novel therapeutic targets to potentiate anti-tumor immunity. My ultimate goal is to become a tenure- track faculty member at a leading academic research institution and conduct NIH funded work contributing to the field of tumor immunology by elucidating anti-tumor immunity and developing novel immunotherapies.

项目概要阻断检查点分子程序性细胞死亡 1 (PD-1) 及其配体的免疫疗法 PD-L1彻底改变了癌症治疗；然而，相当多的患者表现出耐药性免疫疗法，无论是从头开始还是在初始缓解后疾病复发[1-3]。免疫治疗难治性案例促使人们深入了解耐药机制，这最终应该导致新的策略扩大临床疗效。原发性耐药与肿瘤内缺乏免疫细胞浸润有关微环境（TME），这一观察促使人们对肿瘤和宿主进行更深入的研究调节自发 T 细胞激活和浸润肿瘤部位程度的因素。相关一患者间异质性的来源是免疫调节中多态性 (SNP) 的可变存在基因，其中许多基因先前已与自身免疫倾向相关。在该拟议计划的 F99 阶段，我将评估针对自身免疫相关疾病的效用基因以增加免疫治疗功效。酪氨酸蛋白磷酸酶非受体 22 型中的 SNP (PTPN22) 基因被认为是除了人类突变之外患自身免疫性疾病的最大风险白细胞抗原位点[4-6]。 PTPN22 负向调节多个免疫区室的激活，功能丧失变异导致小鼠和人类免疫细胞活化增强[7-8]。这免疫活性的增加归因于活化的 CD8+ T 细胞的扩增，然而，据报道，日期已经使用了全局基因敲除小鼠（KO），混淆了 PTPN22 在其他细胞谱系中的特定作用与抗肿瘤免疫相关，特别是骨髓细胞。因此，我们开发了 PTPN22fl/fl 小鼠来研究其通过条件 KO 小鼠模型对不同免疫细胞类型产生影响。我假设 PTPN22 丢失通过以下方式增强 DC 激活抗原特异性 CD8+ T 细胞的能力： 1) 改善 tdLN 或 TME 中的募集和/或生存信号传导，以及 2) PTPN22 的缺失巨噬细胞还可以增强抗肿瘤免疫力。在拟议计划的 K00 阶段，我的目标是确定控制抗肿瘤免疫和免疫治疗功效，通过 1) 识别与功能变异相关的自身免疫相关 SNP 肿瘤免疫浸润增加，2) 表征这些靶点对肿瘤进展的影响以及通过使用条件 KO 小鼠进行功能研究的免疫治疗反应。这项工作有潜力阐明增强抗肿瘤免疫力的新治疗靶点。我的最终目标是成为一名终身教授—— 跟踪领先学术研究机构的教员并开展 NIH 资助的工作，为通过阐明抗肿瘤免疫和开发新型免疫疗法，进入肿瘤免疫学领域。