Chemokines are key mediators of inflammation and are involved in both
extrinsic and intrinsic pathway of cancer. Their main function is to induce leukocyte
migration through the binding of specific seven transmembrane receptors. Beside
canonical chemokine receptor a smaller family of atypical chemokine receptors was
described. ACKR2 binds with high affinity a broad panel of CC inflammatory
chemokines mediating their internalization and intracellular degradation. Due to its
chemokine scavenging activity, ACKR2 plays a protective role in chronic
inflammation and in the extrinsic pathway of cancer.
The objective of my thesis was to investigate the role of ACKR2 in the intrinsic
pathway of cancer using the NeuT (HER2) murine model of oncogene-driven breast
cancer crossed with ACKR2 KO mice. In this model, we found that ACKR2 plays a
dual an opposite role. It slows the primary tumor development while it promotes lung
metastasis. We found the same phenotype on metastasis using the orthotopically
transplanted 4T1 mammary carcinoma and melanoma B16F10 cell lines were we
demonstrated that ACKR2 expression in the hematopoietic compartment acts as a
negative regulator of the mobilization of neutrophils with anti-metastatic function.
In the last part of my thesis we also investigated the phenotype of circulating
and tumor associated neutrophils (TANs) in glioma patients, a tumor context
characterized by blood neutrophilia and a general immunosuppressive state. We found
a higher grade of neutrophilia and an increased rate of immature neutrophils in high
grade comparing low grade glioma patients. Finally, we found that the relative
abundance of circulating neutrophils on total leukocytes positively correlates with
relative abundance of TANs.
Collectively taken, these results indicate that neutrophils are a heterogeneous
population with both pro and anti-tumoral functions. Targeting of neutrophils in cancer
context represent a potential therapeutic approach that limit their pro-tumoral role
unleashing the anti-tumoral and anti-metastatic potential