A Multikinase and DNA-PK Inhibitor Combination Immunomodulates Melanomas, Suppresses Tumor Progression, and Enhances Immunotherapies

摘要

Combination therapies have the potential to improve outcomes in melanoma patients but have not yet been clinically efficacious. Here, we used high-throughput flow cytometrybased screening to identify and characterize candidate therapies that might synergize with and augment T-cell immunotherapy efficacy. Two lead therapies, regorafenib (Reg) and NU7441, were selected based on their ability to alter a variety of immunomodulatory proteins, including CD55, CD73, CD155, programmed death-ligand 1 (PD-L1), nerve growth factor receptor (NGFR), and HLA class I in a heterogeneous panel of melanomas. The therapies also upregulated several melanoma antigens, inhibited proliferation, and perturbed activation of oncogenic signaling pathways in melanomas. T cells treated with the therapies proliferated normally and exhibited a favorably altered phenotype, including increased CD25, CD28, inducible T-cell costimulator (ICOS), and reduced expression of coinhibitory receptors. Cytokine production was also increased in treated T cells. When administered in mice, REg suppressed melanoma progression in a CD8(+) T cell-dependent manner when used alone and with various immunotherapies. Additionally, Reg altered the number, phenotype, and function of various T-cell subsets in the tumor microenvironment. These studies reveal that Reg and NU7441 influence the immunobiology of both tumor cells and T cells and enhance the efficacy of various immunotherapies. (C) 2017 AACR.