Interleukin-8: A chemokine at the intersection of cancer plasticity, angiogenesis, and immune suppression

Abstract

Tumor progression relies on the ability of cancer cells to effectively invade surrounding tissues and propagate. Among the many mechanisms that contribute to tumor progression is the epithelial-to-mesenchymal transition (EMT), a phenotypic plasticity phenomenon that increases the cancer cells’ motility and invasiveness and influences their surrounding microenvironment by promoting the secretion of a variety of soluble factors. One such factor is IL-8, a chemokine with multiple pro-tumorigenic roles within the tumor microenvironment (TME), including stimulating proliferation or transformation of tumor cells into a migratory or mesenchymal phenotype. Further, IL-8 can increase tumor angiogenesis or recruit larger numbers of immunosuppressive cells to the tumor. Prognostically, observations in many tumor types show that patients with higher levels of IL-8 at baseline experience worse clinical outcomes. Additionally, studies have shown that the chemokine directly contributes to the development of resistance to both chemotherapy and molecularly targeted agents. More recently, clinical studies evaluating levels of IL-8 in patients receiving immune checkpoint inhibition (ICI) therapy deduced that myeloid tumor infiltration driven by IL-8 contributes to resistance to ICI agents and that peripheral IL-8 can predict outcomes to ICI therapy. Further, pre-clinical data demonstrate that targeting IL-8 or its receptors enables improved tumor killing by immune cells, and treatment strategies combining blockade of the IL-8/IL-8R axis with ICI ultimately improve anti-tumor efficacy. Based on these results and the prognostic capacity of IL-8, there are a number of ongoing clinical trials evaluating the addition of IL-8 targeting strategies to immune-based therapies.