Chemokines as Regulators of Neutrophils: Focus on Tumors, Therapeutic Targeting, and Immunotherapy

Simple Summary Neutrophils are the main leukocyte subset present in human blood and play a fundamental role in the defense against infections. Neutrophils are also an important component of the tumor stroma because they are recruited by selected chemokines produced by both cancer cells and other cells of the stroma. Even if their presence has been mostly associated with a bad prognosis, tumor-associated neutrophils are present in different maturation and activation states and can exert both protumor and antitumor activities. In addition, it is now emerging that chemokines not only induce neutrophil directional migration but also have an important role in their activation and maturation. For these reasons, chemokines and chemokine receptors are now considered targets to improve the antitumoral function of neutrophils in cancer immunotherapy. Neutrophils are an important component of the tumor microenvironment, and their infiltration has been associated with a poor prognosis for most human tumors. However, neutrophils have been shown to be endowed with both protumor and antitumor activities, reflecting their heterogeneity and plasticity in cancer. A growing body of studies has demonstrated that chemokines and chemokine receptors, which are fundamental regulators of neutrophils trafficking, can affect neutrophil maturation and effector functions. Here, we review human and mouse data suggesting that targeting chemokines or chemokine receptors can modulate neutrophil activity and improve their antitumor properties and the efficiency of immunotherapy.