@article {Horne000326, author = {Lucas A Horn and Jeffrey Riskin and Heidi A Hempel and Kristen Fousek and Hanne Lind and Duane H Hamilton and Kristen K McCampbell and Dean Y Maeda and John A Zebala and Zhen Su and Jeffrey Schlom and Claudia Palena}, title = {Simultaneous inhibition of CXCR1/2, TGF-β, and PD-L1 remodels the tumor and its microenvironment to drive antitumor immunity}, volume = {8}, number = {1}, elocation-id = {e000326}, year = {2020}, doi = {10.1136/jitc-2019-000326}, publisher = {BMJ Specialist Journals}, abstract = {Background Despite the success of immune checkpoint blockade therapy in the treatment of certain cancer types, only a small percentage of patients with solid malignancies achieve a durable response. Consequently, there is a need to develop novel approaches that could overcome mechanisms of tumor resistance to checkpoint inhibition. Emerging evidence has implicated the phenomenon of cancer plasticity or acquisition of mesenchymal features by epithelial tumor cells, as an immune resistance mechanism.Methods Two soluble factors that mediate tumor cell plasticity in the context of epithelial-mesenchymal transition are interleukin 8 (IL-8) and transforming growth factor beta (TGF-β). In an attempt to overcome escape mechanisms mediated by these cytokines, here we investigated the use of a small molecule inhibitor of the IL-8 receptors CXCR1/2, and a bifunctional agent that simultaneously blocks programmed death ligand 1 (PD-L1) and traps soluble TGF-β.Results We demonstrate that simultaneous inhibition of CXCR1/2, TGF-β, and PD-L1 signaling synergizes to reduce mesenchymal tumor features in murine models of breast and lung cancer, and to markedly increase expression of tumor epithelial E-cadherin while reducing infiltration with suppressive granulocytic myeloid-derived suppressor cells, significantly enhancing T-cell infiltration and activation in tumors, and leading to improved antitumor activity.Conclusions This study highlights the potential benefit of combined blockade of CXCR1/2 and TGF-β signaling for modulation of tumor plasticity and potential enhancement of tumor responses to PD-L1 blockade. The data provide rationale for the evaluation of this novel approach in the clinic.}, URL = {https://jitc.bmj.com/content/8/1/e000326}, eprint = {https://jitc.bmj.com/content/8/1/e000326.full.pdf}, journal = {Journal for ImmunoTherapy of Cancer} }