ACKR2 in hematopoietic precursors as a checkpoint of neutrophil release and anti-metastatic activity

Matteo Massara,Francesca Ficara,Camilla Recordati,Valeria Mollica Poeta,Massimo Locati,Elisa Setten,Marina Sironi,Nicoletta Caronni,Benedetta Savino,Ornella Bonavita,Laura Crisafulli,Alberto Mantovani,Raffaella Bonecchi

doi:10.1038/s41467-018-03080-8

Abstract

Atypical chemokine receptors (ACKRs) are regulators of leukocyte traffic, inflammation, and immunity. ACKR2 is a scavenger for most inflammatory CC chemokines and is a negative regulator of inflammation. Here we report that ACKR2 is expressed in hematopoietic precursors and downregulated during myeloid differentiation. Genetic inactivation of ACKR2 results in increased levels of inflammatory chemokine receptors and release from the bone marrow of neutrophils with increased anti-metastatic activity. In a model of NeuT-driven primary mammary carcinogenesis ACKR2 deficiency is associated with increased primary tumor growth and protection against metastasis. ACKR2 deficiency results in neutrophil-mediated protection against metastasis in mice orthotopically transplanted with 4T1 mammary carcinoma and intravenously injected with B16F10 melanoma cell lines. Thus, ACKR2 is a key regulator (checkpoint) of mouse myeloid differentiation and function and its targeting unleashes the anti-metastatic activity of neutrophils in mice.

Highlights

Atypical chemokine receptors (ACKRs) are regulators of leukocyte traffic, inflammation, and immunity
We found that ACKR2 is expressed in hematopoietic progenitor cells (HPCs) and that it serves as a key regulator of myeloid differentiation and function
As depletion and adoptive transfer experiments clearly pointed to neutrophils as the key elements responsible for protection against metastasis observed in the absence of ACKR2, we evaluated their reactive oxygen species (ROS) production, one of the main mechanism of tumor cell-killing

Summary

Introduction

Atypical chemokine receptors (ACKRs) are regulators of leukocyte traffic, inflammation, and immunity. ACKR2 is a scavenger for most inflammatory CC chemokines and is a negative regulator of inflammation. Genetic inactivation of ACKR2 results in increased levels of inflammatory chemokine receptors and release from the bone marrow of neutrophils with increased anti-metastatic activity. ACKR2 is a key regulator (checkpoint) of mouse myeloid differentiation and function and its targeting unleashes the anti-metastatic activity of neutrophils in mice. Oncogene activation drives chemokine production and leukocyte recruitment in tumors epidemiologically unrelated to inflammatory conditions[3]. The chemokine repertoire expressed by tumor cells impacts on secondary seeding at distant sites such as the brain or lymph nodes[6]. Inflammatory chemokines precondition the metastatic niche and drive tumor cell seeding at sites of secondary localization[7]

Methods

Results

Conclusion