Simultaneous inhibition of CXCR1/2, TGF-β, and PD-L1 remodels the tumor and its microenvironment to drive antitumor immunity

Abstract

BackgroundDespite 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.MethodsTwo 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.ResultsWe 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.ConclusionsThis 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.

Expression and clinical significance of PD-L1, B7-H3, B7-H4 and VISTA in craniopharyngioma

“… 23 The expanding list of B7 family members includes CTLA-4 (ligands B7.1 and B7.2), PD-1 (ligands PD-L1 and PD-L2), TIM3 (ligands CEACAM-1, HMGB1 and galectin-9), TIGIT (ligands CD155 and CD112), BTLA (ligand HVEM), B7-H3, B7-H4 and VISTA. 24 25 In this study, we investigated the expression level of B7 family ligands/receptors in CPs. More importantly, we have discovered some associations between B7 family ligands/receptors expression and clinical features of CPs.…”

Therapeutic targeting of TGF-β in cancer: hacking a master switch of immune suppression

“…The TgfβrII module was able to efficiently trap the Tgf-β1, -2 and -3 isoforms [145]. In murine breast and lung cancer models, treatment with bintrafusp alfa was combined with small molecule inhibitors targeting Cxcr1/2; the latter blocked interleukin 8 (IL-8) activity and thereby prevented the acquisition of mesenchymal properties by cancer cells [147]. This combination improved anti-tumour efficacy of either monotherapy, leading to decreased tumour volumes and increased infiltration of T and NK cells in the TME [147].…”

Transforming Growth Factor-β: A Multifunctional Regulator of Cancer Immunity

“…In an ongoing phase I clinical trial (NCT02517398), bintrafusp alfa has demonstrated good clinical response, safety, and tolerance in advanced head and neck squamous cell carcinoma (HNSCC) that progressed after platinum therapy [ 150 ]. In addition, a joint targeting of CXCR1/2, TGF-β1, and PD-L1 using the CXCR1/2 inhibitor SX-682 and bintrafusp alfa also reduces EMT, enhances the infiltration of effector T cells and promotes the blockade of granulocytic myeloid cells in breast and lung cancer mouse models in vivo [ 151 ]. Similarly, bifunctional fusion antibodies that simultaneously target the immune checkpoint and disable TGF-β signalling can significantly enhance the efficacy of cancer immunotherapy [ 152 ].…”