权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mechanisms of Tumor Derived Neutrophil Induced Apoptosis in Lymphocytes

肿瘤源性中性粒细胞诱导淋巴细胞凋亡的机制

基本信息

批准号：
10631181
负责人：
A McGarry Houghton
金额：
$ 44.8万
依托单位：
FRED HUTCHINSON CANCER CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-17 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10631181
关键词：
Accounting Address Antigens Antitumor Response Apoptosis Atypical lymphocyte Behavior Biological Models CD8-Positive T-Lymphocytes Cancer Etiology Cancer Patient Cell Communication Cell Lineage Cell physiology Cells Cessation of life Chemotaxis Clinical Clinical Trials Data Gene Expression Profile Genetically Engineered Mouse Human Immune Immune checkpoint inhibitor Immune response Immunohistochemistry In Vitro Infiltration Leukocyte Elastase Lung Adenocarcinoma Lung Neoplasms Lymphocyte Lymphocyte Function Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Mediating Mediator of activation protein Methodology Microfluidic Microchips Modeling Mus Mutate Myelogenous Myeloid Cells Myeloid-derived suppressor cells Nature Neutrophil Activation Non-Small-Cell Lung Carcinoma PD-1/PD-L1 Peroxidases Pharmaceutical Preparations Phenotype Population Role Series Solid Neoplasm Specimen Spleen Structure of parenchyma of lung System Testing Therapeutic Tumor-Derived Work antagonist anti-PD-1 anti-PD-L1 antibodies anti-PD-L1 therapy anti-PD1 therapy apoptosis in lymphocytes arginase base cancer type cell type checkpoint therapy cohort design discounting exhaust exhaustion immune checkpoint immune checkpoint blockade improved in vitro Model in vivo liquid crystal polymer lymphocyte proliferation macrophage monocyte mortality neoplastic cell neutrophil novel novel therapeutics peripheral blood prevent response success tumor tumor microenvironment

项目摘要

ABSTRACT Although immune checkpoint inhibitor (ICI) therapy has been a tremendous clinical success, just ~20% of non- small cell lung cancer (NSCLC) patients respond to anti-PD1/PDL1 therapy. In efforts to improve upon this figure, the field has launched over 800 clinical trials (across all cancer types) testing novel therapeutics in conjunction with immune checkpoint blockade. Unfortunately, such trials have been based largely on theoretical considerations and not by data obtained from actual human cancer specimens. Notably, very few of these trials address myeloid lineage cells and none of them address the neutrophil lineage. Our group recently undertook a comprehensive immune phenotyping project to identify potential immune suppressive factors in human NSCLC. We found that neutrophils were the most prevalent immune cell type out of the 51 immune cell types and subtypes assessed. More importantly, the presence of neutrophil lineage cells inversely correlated with CD8+ lymphocyte content within the TME. Here, we will show that tumor derived neutrophils antagonize CD8+ lymphocyte function both in vitro and in vivo and determine the mechanisms by which they do so. Furthermore, we will perform clinical trials in tumor bearing mice to show that neutrophil depleting drugs will improve the efficacy of immune checkpoint inhibitor therapy.

抽象的尽管免疫检查点抑制剂 (ICI) 疗法在临床上取得了巨大成功，但只有约 20% 的非免疫检查点抑制剂 (ICI) 疗法在临床上取得了巨大成功。小细胞肺癌 (NSCLC) 患者对抗 PD1/PDL1 治疗有反应。正在努力改进这一点如图所示，该领域已启动 800 多项临床试验（涵盖所有癌症类型），测试新疗法与免疫检查点阻断相结合。不幸的是，此类试验主要基于理论上的考虑，而不是从实际人类癌症标本中获得的数据。值得注意的是，极少数这些试验针对的是骨髓谱系细胞，但没有一个针对中性粒细胞谱系。我们组最近进行了全面的免疫表型分析项目，以确定潜在的免疫抑制因素人类非小细胞肺癌。我们发现中性粒细胞是 51 种免疫细胞中最常见的免疫细胞类型评估的类型和亚型。更重要的是，中性粒细胞谱系细胞的存在呈负相关 TME 内 CD8+ 淋巴细胞含量。在这里，我们将证明肿瘤来源的中性粒细胞拮抗 CD8+ 淋巴细胞在体外和体内均发挥作用，并决定其发挥作用的机制。此外，我们将在荷瘤小鼠中进行临床试验，以表明中性粒细胞消耗药物将提高免疫检查点抑制剂治疗的疗效。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Annexin A2/TLR2/MYD88 pathway induces arginase 1 expression in tumor-associated neutrophils.

DOI：
10.1172/jci153643
发表时间：
2022-11-15
期刊：
JOURNAL OF CLINICAL INVESTIGATION
影响因子：
15.9
作者：
Zhang, Huajia;Zhu, Xiaodong;Friesen, Travis J.;Kwak, Jeff W.;Pisarenko, Tatyana;Mekvanich, Surapat;Velasco, Mark A.;Randolph, Timothy W.;Kargl, Julia;Houghton, A. McGarry
通讯作者：
Houghton, A. McGarry