Neutrophil heterogeneity in cancer

Abstract

Neutrophils are abundant in a wide range of cancer types and are classically considered to be tumor-promoting cells associated with poor clinical outcomes. However, emerging evidence suggests that tumor-associated neutrophils can exhibit anti-tumor, as well as pro-tumor functions. These contrasting reports suggest a need to better understand neutrophil diversity, and the mechanisms underlying the development of these divergent functional states. The first study presented in this dissertation focuses on a population of SiglecFhi neutrophils found in lung tumors, which displays several pro-tumor phenotypes and directly contributes to primary tumor growth. Our goal was to further define the identity of SiglecFhi neutrophils and better understand the response mediated by these cells in vivo. We found SiglecFhi neutrophils to be mature, non-proliferating cells that are long-lived at the tumor site and display fundamental features that diverge from previously reported neutrophil populations. The second study presented in this dissertation investigates whether neutrophils with opposing functions co-exist in tumors, and whether specific anti-tumor neutrophil states can be harnessed in therapy. We found that successful immunotherapy treatments acutely expanded a Sellhi neutrophil state which displayed an interferon gene signature. Sellhi neutrophils were required for successful responses to immunotherapy treatment, and were dependent on the interferon responsive transcription factor Irf1, as well as interactions between T and dendritic cells. In addition, Sellhi neutrophils displayed putative progenitors at the tumor site that were distinct from SiglecFhi neutrophil progenitors. Together these findings further our understanding of SiglecFhi pro-tumor neutrophils, and establish a crucial role for Sellhi neutrophils in mediating effective cancer immunotherapy. This will be important in determining how we could potentially manipulate these neutrophils to promote anti-tumor responses in patients.