Neutrophils are the most abundant white blood cells and are the first recruited to inflammatory sites. Neutrophils are an important component of the tumor stroma and can exert both anti-tumoral and pro-tumoral activities, depending on their maturation and activation state. In human gliomas, the number of circulating and infiltrating neutrophils correlates with the severity of the disease, indicating a prognostic and possible pro-tumoral role for these leukocytes. In glioma preclinical models, neutrophils promote tumor growth and orchestrate the resistance to anti-angiogenic therapies. Nevertheless, recent data indicate that neutrophils can be activated to directly kill tumor cells or to orchestrate the anti-tumoral response. Here, we review current knowledge about the role of neutrophils in glioma and their possible involvement in new strategies to improve current cancer therapies.

The chemokine system is a fundamental component of cancer-related inflammation involved in all stages of cancer development. It controls not only leukocyte infiltration in primary tumors but also angiogenesis, cancer cell proliferation, and migration to metastatic sites. Atypical chemokine receptors are a new, emerging class of regulators of the chemokine system. They control chemokine bioavailability by scavenging, transporting, or storing chemokines. They can also regulate the activity of canonical chemokine receptors with which they share the ligands by forming heterodimers or by modulating their expression levels or signaling activity. Here, we summarize recent results about the role of these receptors (atypical chemokine receptor 1/Duffy antigen receptor for chemokine, atypical chemokine receptor 2/D6, atypical chemokine receptor 3/CXC-chemokine receptor 7, and atypical chemokine receptor 4/CC-chemokine receptor-like 1) on the tumorigenesis process, indicating that their effects are strictly dependent on the cell type on which they are expressed and on their coexpression with other chemokine receptors. Indeed, atypical chemokine receptors inhibit tumor growth and progression through their activity as negative regulators of chemokine bioavailability, whereas, on the contrary, they can promote tumorigenesis when they regulate the signaling of other chemokine receptors, such as CXC-chemokine receptor 4. Thus, atypical chemokine receptors are key components of the regulatory network of inflammation and immunity in cancer and may have a major effect on anti-inflammatory and immunotherapeutic strategies.

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.

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The lymphatic system plays an important role in the induction of the immune response by transporting antigens, inflammatory mediators, and leukocytes from peripheral tissues to draining lymph nodes. It is emerging that lymphatic endothelial cells (LECs) are playing an active role in this context via the expression of chemokines, inflammatory mediators promoting cell migration, and chemokine receptors. Particularly, LECs express atypical chemokine receptors (ACKRs), which are unable to promote conventional signaling and cell migration while they are involved in the regulation of chemokine availability. Here, we provide a summary of the data on the role of ACKR2 expressed by lymphatics, indicating an essential role for this ACKRs in the regulation of the inflammation and the immune response in different pathological conditions, including infection, allergy, and cancer.

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