Mechanisms of Tumor Derived Neutrophil Induced Apoptosis in Lymphocytes

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.