Mechanisms of Tumor Derived Neutrophil Induced Apoptosis in Lymphocytes

摘要 尽管免疫检查点抑制物(ICI)治疗在临床上取得了巨大的成功，但只有~20%的非 小细胞肺癌(NSCLC)患者对抗PD1/PDL1治疗有反应。在努力改善这一点上 数字，该领域已经启动了800多项临床试验(涉及所有癌症类型)，测试新的治疗方法 结合免疫检查站封锁。不幸的是，这样的试验主要是基于 理论上的考虑，而不是从实际的人类癌症样本中获得的数据。值得注意的是，很少有 这些试验涉及髓系细胞，但没有一项涉及中性粒细胞系。我们的小组最近 开展了一项全面的免疫表型项目，以确定潜在的免疫抑制因素 人类非小细胞肺癌。我们发现在51个免疫细胞中，中性粒细胞是最常见的免疫细胞类型。 评估的类型和子类型。更重要的是，中性粒细胞系细胞的存在呈负相关 与TME内CD8+淋巴细胞含量有关。在这里，我们将展示肿瘤来源的中性粒细胞拮抗 CD8+淋巴细胞在体外和体内的功能，并确定其作用机制。 此外，我们将在荷瘤小鼠身上进行临床试验，以表明中性粒细胞耗竭药物将 提高免疫检查点抑制剂治疗的疗效。

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.