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

• 批准号: 10601352
• 负责人: A McGarry Houghton
• 金额: $ 25.69万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 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/10601352
• 关键词: Mechanisms; Tumor; Derived; Neutrophil; Induced

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.

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。为了改进这一点 据统计，该领域已经启动了800多项临床试验（涵盖所有癌症类型），测试新的治疗方法， 与免疫检查点阻断结合。不幸的是，这种审判主要是基于 理论上的考虑，而不是从实际的人类癌症标本中获得的数据。值得注意的是， 这些试验针对髓系细胞，没有一个针对嗜中性粒细胞系。我们组最近 进行了一项全面的免疫表型分析项目，以确定潜在的免疫抑制因素， 人NSCLC。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与 TME内的CD 8+淋巴细胞含量。在这里，我们将表明，肿瘤源性中性粒细胞拮抗 CD 8+淋巴细胞在体外和体内都有功能，并决定了它们这样做的机制。 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。