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Cancer Immunol Res ; 5(9): 790-803, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28775208

RESUMO

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 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. Cancer Immunol Res; 5(9); 790-803. ©2017 AACR.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Cromonas/administração & dosagem , Imunoterapia , Melanoma/tratamento farmacológico , Morfolinas/administração & dosagem , Compostos de Fenilureia/administração & dosagem , Piridinas/administração & dosagem , 5'-Nucleotidase/antagonistas & inibidores , 5'-Nucleotidase/imunologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/imunologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Antígenos CD55/antagonistas & inibidores , Antígenos CD55/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Proliferação de Células/efeitos dos fármacos , Cromonas/imunologia , Citometria de Fluxo , Genes MHC Classe I/imunologia , Humanos , Imunomodulação/efeitos dos fármacos , Melanoma/imunologia , Melanoma/patologia , Camundongos , Morfolinas/imunologia , Compostos de Fenilureia/imunologia , Piridinas/imunologia , Receptores Virais/antagonistas & inibidores , Receptores Virais/imunologia , Subpopulações de Linfócitos T/imunologia , Microambiente Tumoral/efeitos dos fármacos
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