Abstract:
Notwithstanding the well-recognized involvement of chronic neutrophilic inflammation in
the initiation phase of many types of epithelial cancers, a growing body of evidence has also implicated
these cells in the pathogenesis of the later phases of cancer development, specifically progression
and spread. In this setting, established tumors have a propensity to induce myelopoiesis and to
recruit neutrophils to the tumor microenvironment (TME), where these cells undergo reprogramming
and transitioning to myeloid-derived suppressor cells (MDSCs) with a pro-tumorigenic phenotype.
In the TME, these MDSCs, via the production of a broad range of mediators, not only attenuate the
anti-tumor activity of tumor-infiltrating lymphocytes, but also exclude these cells from the TME.
Realization of the pro-tumorigenic activities of MDSCs of neutrophilic origin has resulted in the
development of a range of adjunctive strategies targeting the recruitment of these cells and/or the
harmful activities of their mediators of immunosuppression. Most of these are in the pre-clinical or
very early clinical stages of evaluation. Notable exceptions, however, are several pharmacologic,
allosteric inhibitors of neutrophil/MDSC CXCR1/2 receptors. These agents have entered late-stage
clinical assessment as adjuncts to either chemotherapy or inhibitory immune checkpoint-targeted
therapy in patients with various types of advanced malignancy. The current review updates the
origins and identities of MDSCs of neutrophilic origin and their spectrum of immunosuppressive
mediators, as well as current and pipeline MDSC-targeted strategies as potential adjuncts to cancer
therapies. These sections are preceded by a consideration of the carcinogenic potential of neutrophils.
