Abstract 1508: Primary tumors induce neutrophil extracellular traps with targetable metastasis promoting effects

Abstract

Targeting the dynamic tumor immune microenvironment can provide effective therapeutic strategies for cancer. Neutrophils (polymorphonuclear neutrophils, PMNs) are the predominant circulating leukocyte population in humans and are vital to fight infection. Despite mounting evidence that PMNs can promote tumor progression, depleting PMNs is not a viable therapeutic option. Neutrophil extracellular traps (NETs) are networks of extracellular neutrophil DNA fibers that are capable of trapping tumor cells and promoting their growth and their metastasis. Targeting NETs can therefore be a potentially successful therapeutic option to block the tumor promoting functions of PMNs. Here we demonstrate that circulating NET levels are elevated in esophageal, gastric and lung cancer patients compared to healthy controls. This increase correlates with disease stage and NET levels are independent predictors of advanced stage. Using pre-clinical murine models of lung and colon cancer, we observe elevated NET levels in tumor bearing mice compared to non-tumor bearing mice; these levels correlated with tumor size. NET levels significantly decrease following tumor resection or treatment with DNase1, a NET degrader, or neutrophil elastase inhibitor (NEi), a NET inhibitor. NET levels do not rise following tumor inoculation in peptidyl arginine deiminase-IV knock out (PAD4-/-) mice; PAD4 being an enzyme essential for citrullination of histones, a crucial step in NET release. Moreover, PMNs from tumor bearing mice are more primed for NETosis than PMNs from non-tumor bearing mice or NEi-treated or PAD4-/- tumor bearing mice. Finally, elevated in vivo hepatic adhesion and spontaneous liver and lung metastases are observed in tumor bearing mice compared to DNase1- or NEi-treated or PAD4-/- tumor bearing mice. Therefore, inhibiting NETs represents a promising strategy to impede metastatic dissemination in several types of cancer patients. Citation Format: Roni F. Rayes, Jack G. Mouhanna, Ioana Nicolau, Phil Vourtzoumis, Carson Wong, Jules Eustache, France Bourdeau, Betty Giannias, Aya Siblini, Emma Lee, Veena Sangwan, Simon Rousseau, Daniela Quail, Logan Walsh, Nicholas Bertos, Jonathan Cools-Lartigue, Lorenzo E. Ferri, Jonathan D. Spicer. Primary tumors induce neutrophil extracellular traps with targetable metastasis promoting effects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1508.

Diagnostic, Therapeutic Predictive, and Prognostic Value of Neutrophil Extracellular Traps in Patients With Gastric Adenocarcinoma

“…For example, the use of plasma included autoimmune small-vessel vasculitis, colorectal cancer and hepatocellular cancer (11,13,14). Besides, the use of serum contained lymphoma, esophageal adenocarcinoma, and lung adenocarcinoma (12,15). Compared with the serum, the plasma contains coagulation factors and fibrinogen.…”

“…Therefore, NETs may also exist in the GC microenvironment. In addition, a recent study reported significantly higher PB levels of NETs in 25 advanced esophagogastric adenocarcinoma patients than in 12 patients with local disease (15). Nevertheless, there is currently a lack of large-sample research data.…”

Immunometabolic reprogramming, another cancer hallmark

“…However, immunosuppressive mediators, including TGF-b released at later stages of the tumor, polarize antitumor N1 TANs to pro-tumor N2 TANs (158-160). Also, the glutamine and proline uptake in immature low-density neutrophils (iLDNs) supports their pro-metastasis action inducing NETosis under hypoxic and glucose-deprived conditions (Figure 4) (161,162). NETs promote cancer growth, progression, and metastasis and provide a protective shield to them through different mechanisms discussed somewhere else (163).…”

Biomarkers of peripheral blood neutrophil extracellular traps in the diagnosis and progression of malignant tumors

“…NETs have been detected in primary tumors, metastatic tumor tissues, and the circulatory system of tumors. [18][19][20] This may be because NETs are degraded by extracellular DNA enzymes into soluble products that are released into the peripheral blood. 21 Studies have shown that changes in infiltrated NETs in tumor tissue correlate with changes in NETs in the peripheral blood.…”

“…NETs have been detected in primary tumors, metastatic tumor tissues, and the circulatory system of tumors 18–20 . This may be because NETs are degraded by extracellular DNA enzymes into soluble products that are released into the peripheral blood 21 .…”