Multiple cytokines, chemokines, and growth factors play critical roles as mediators of paracrine signals between the tumor and cellular components of the tumor microenvironment (TME), ultimately leading to tumor growth, survival, and progression. One of the soluble factors that has a multifaceted role in cancer progression is the chemokine IL-8 (CXCL8), which signals through the receptors CXCR1 and CXCR2.Abnormally high expression of IL-8 is found in multiple cancer types, including in triple negative breast, colorectal, lung, and head and neck tumors, among others. IL-8 can foster tumor progression by various means, including (a) promoting the trafficking of immune-suppressive cells to the tumor microenvironment, mainly granulocytic myeloid-suppressor cells (G-MDSCs), which exert a suppressive role on anti-tumor immunity; (b) promoting phenotypic plasticity in carcinoma cells via changes from an epithelial into a mesenchymal-like state; and (c) increasing the survival of cancer stem-like cell populations in the tumor. Tumor phenotypic plasticity has been linked to advanced tumor stage, presence of metastases, poor prognosis in numerous cancer types, and tumor resistance to anti-cancer therapies, including chemotherapy and small molecule-targeted therapies. Recent work has also shown that upregulation of IL-8 and enhanced mesenchymal tumor features are enriched in tumors that are resistant to checkpoint inhibitor therapy. In agreement, our laboratory has demonstrated a role for IL-8 expression in tumor resistance to lysis by immune effector cells. The multifaceted roles of IL-8 in cancer make it a promising therapeutic target. Blockade of IL-8 signaling may be achieved by direct neutralization of IL-8 via a monoclonal antibody or via inhibition of its receptors. Our laboratory has now demonstrated a role for IL-8 in the context of acquired resistance to EGFR inhibition and in the context of acquired resistance to chemotherapies in preclinical models of lung cancer. Alleviation of IL-8 signaling via a neutralizing antibody was shown to reduce mesenchymal features of the resistant cells, and markedly enhanced their sensitivity to therapies. Our group has also shown that neutralization of IL-8 via a monoclonal anti-IL8 antibody is able to revert mesenchymal features in claudin-low, triple negative tumor models, resulting in enhanced immune-mediated lysis with NK and antigen-specific T cells in vitro and reduced tumor infiltration with G-MDSC and improved responses to chemotherapy in vivo. Current work in our laboratory is evaluating inhibition of the CXCR1/2 receptors via the use of the small molecule inhibitor SX-682, as an alternative approach to abrogate signaling mediated not only by IL-8 but also by all other chemokines of the same family that bind to these receptors. In addition to IL-8, the pleiotropic cytokine TGF-β is a driver of phenotypic plasticity and cancer progression and has been implicated as a driver of T-cell exclusion from tumors. Our current experiments are exploring the hypothesis that by reducing mesenchymal features in the tumor via inhibition of IL-8 and/or TGF-β signaling we could enhance the anti-tumor efficacy of the PD-1/PD-L1 axis blockade.

Citation Format: Lucas A Horn, Hanne Lind, Heidi Hempel, Kristen Fousek, Claudia Palena. IL-8 in tumor progression [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr CN08-01. doi:10.1158/1535-7163.TARG-19-CN08-01