The occurrence of phenotypic plasticity in carcinomas, which results in the acquisition of mesenchymal features by epithelial cancer cells, associates with a poor prognosis and has been described as a mechanism of primary resistance and failure to treatment with checkpoint blockade immunotherapy targeting the PD-1/PD-L1 pathway. IL-8 and TGF-β are two of the factors that mediate phenotypic plasticity in epithelial tumors to promote an immune-suppressive microenvironment. Here we report on an immunotherapy approach aimed at overcoming escape mechanisms mediated by IL-8 and TGF-β accumulation in the tumor microenvironment via the use of two clinical-stage agents: SX-682, a dual CXCR1/2 small-molecule inhibitor, with the bifunctional anti-PD-L1/TGFβRII agent, bintrafusp alfa (M7824) that simultaneously blocks PD-L1 while trapping soluble TGF-β. We demonstrate that the concurrent inhibitions of CXCR1/CXCR2, TGF-β, and PD-L1 signaling synergize 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 (G-MDSC), significantly enhancing CD4+ and CD8+ T-cell infiltration and activation in tumors, and leading to improved antitumor activity. This combination approach was effective in tumor models with varying immune cell infiltrates, degrees of plasticity, and responses to immunotherapy. The results of these studies provide the rationale for the future evaluation of this multimodal therapy in the clinic.

Citation Format: Lucas A. Horn, Jeffrey Riskin, Heidi A. Hempel, Hanne Lind, Kristen Fousek, Duane H. Hamilton, Kristen K. McCampbell, Jeffrey Schlom, Claudia Palena. Simultaneous inhibition of CXCR1/CXCR2, TGF-β, and PD-L1 overcomes immune resistance driven by tumor plasticity [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B43.