Anxa2 drives the function of immune suppressive neutrophils in lung cancer

Anxa2 驱动肺癌中免疫抑制性中性粒细胞的功能

• 批准号: 10310981
• 负责人: A McGarry Houghton
• 金额: $ 4.02万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10310981
• 关键词: ANXA2 gene; Accounting; Address; Annexins; CD8-Positive T-Lymphocytes; Cancer Etiology; Cancer Patient; Cell Lineage; Cessation of life; Clinical; Clinical Trials; Data; Human; Immune; Immune checkpoint inhibitor; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Myelogenous; Non-Small-Cell Lung Carcinoma; PD-1/PD-L1; Phenotype; Play; Research Personnel; Role; Scientist; Specimen; Testing; Training; Tumor-Derived; anti-PD-1; anti-PD-L1 therapy; base; cancer type; career; cell type; checkpoint therapy; cohort; graduate student; immune checkpoint blockade; immune function; improved; neutrophil; novel therapeutics; skills; success

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 tumor-derived Annexin-A2 polarizes neutrophils to an immune suppressive phenotype and determine the mechanisms by which it does so. More importantly, this project will provide the necessary training ground for the graduate student to obtain the skills and critical examination of data to progress in his career towards an independent scientist.

摘要 虽然免疫检查点抑制剂（ICI）治疗已经取得了巨大的临床成功，但只有约20%的非免疫检查点抑制剂治疗。 小细胞肺癌（NSCLC）患者对抗PD 1/PDL 1治疗有反应。为了改善这一数字， 该领域已经开展了800多项临床试验（涉及所有癌症类型）， 免疫检查点封锁不幸的是，这种试验主要是基于理论上的， 考虑因素，而不是从实际人类癌症样本获得的数据。值得注意的是，这些试验中 针对髓系细胞，它们都不针对嗜中性粒细胞系。我们小组最近进行了一次 综合免疫表型项目，以确定人类NSCLC中潜在的免疫抑制因子。 我们发现中性粒细胞是51种免疫细胞类型中最普遍的免疫细胞类型， 评估亚型。更重要的是，中性粒细胞谱系细胞的存在与CD 8+呈负相关。 TME内的淋巴细胞含量。在这里，我们将展示肿瘤来源的Annexin-A2将中性粒细胞极化为中性粒细胞。 免疫抑制表型，并确定其机制。更重要的是这个 该项目将提供必要的培训基地，为研究生获得的技能和关键 研究数据，使他的职业生涯朝着独立科学家的方向发展。