Stromal-driven and Amyloid \u03b2-dependent induction of neutrophil extracellular traps modulates tumor growth

Hafsa Munir,Maximilien Euler,Tobias Janowitz,Carla P Martins,Sarah J Welsh,Jacqueline D Shields,James O Jones,Markus Hoffmann

doi:10.1038/s41467-021-20982-2

Abstract

Tumors consist of cancer cells and a network of non-cancerous stroma. Cancer-associated fibroblasts (CAF) are known to support tumorigenesis, and are emerging as immune modulators. Neutrophils release histone-bound nuclear DNA and cytotoxic granules as extracellular traps (NET). Here we show that CAFs induce NET formation within the tumor and systemically in the blood and bone marrow. These tumor-induced NETs (t-NETs) are driven by a ROS-mediated pathway dependent on CAF-derived Amyloid β, a peptide implicated in both neurodegenerative and inflammatory disorders. Inhibition of NETosis in murine tumors skews neutrophils to an anti-tumor phenotype, preventing tumor growth; reciprocally, t-NETs enhance CAF activation. Mirroring observations in mice, CAFs are detected juxtaposed to NETs in human melanoma and pancreatic adenocarcinoma, and show elevated amyloid and β-Secretase expression which correlates with poor prognosis. In summary, we report that CAFs drive NETosis to support cancer progression, identifying Amyloid β as the protagonist and potential therapeutic target.

Highlights

Tumors consist of cancer cells and a network of non-cancerous stroma
Lung and pancreatic FB or Cancer-associated fibroblasts (CAF) conditioned media (CMed) had no impact on neutrophil viability for the duration of treatment while Phorbol 12-myristate 13-acetate (PMA) induced low levels of neutrophil death (Supplementary Fig. 1B)
We demonstrate that neutrophils recruited to the tumor frequently localize to CAF-rich areas, where they are stimulated to generate extracellular traps (NETs) supporting tumor growth

Summary

Introduction

Cancer-associated fibroblasts (CAF) are known to support tumorigenesis, and are emerging as immune modulators. We show that CAFs induce NET formation within the tumor and systemically in the blood and bone marrow. These tumor-induced NETs (t-NETs) are driven by a ROS-mediated pathway dependent on CAF-derived Amyloid β, a peptide implicated in both neurodegenerative and inflammatory disorders. The stroma includes leukocytes, cancer-associated fibroblasts (CAFs), pericytes, blood vessels and lymphatic vessels[1]. CAF-derived IL-6 can induce systemic immunosuppressive effects[13]. These data demonstrate that anticancer immune responses can be modulated by CAFs, and failure of the immune system to control cancer is not solely mediated by cancer cells and the surrounding stroma

Methods

Results

Conclusion