TY - JOUR
T1 - A multikinase and DNA-PK inhibitor combination immunomodulates melanomas, suppresses tumor progression, and enhances immunotherapies
AU - Tsai, Alexander K.
AU - Khan, Asra Y.
AU - Worgo, Christina E.
AU - Wang, Lucy L.
AU - Liang, Yuanyuan
AU - Davila, Eduardo
N1 - Funding Information:
This research was supported by the University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Melanoma Research Foundation, National Cancer Institute (R01CA140917 and T32CA154274), and VA Merit Award BX002142.
Publisher Copyright:
©2017 AACR.
PY - 2017/9
Y1 - 2017/9
N2 - Combination therapies have the potential to improve outcomes in melanoma patients but have not yet been clinically efficacious. Here, we used high-throughput flow cytometry-based 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 CD8þ 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.
AB - Combination therapies have the potential to improve outcomes in melanoma patients but have not yet been clinically efficacious. Here, we used high-throughput flow cytometry-based 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 CD8þ 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.
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U2 - 10.1158/2326-6066.CIR-17-0009
DO - 10.1158/2326-6066.CIR-17-0009
M3 - Article
C2 - 28775208
AN - SCOPUS:85028523364
VL - 5
SP - 790
EP - 803
JO - Cancer immunology research
JF - Cancer immunology research
SN - 2326-6066
IS - 9
ER -