A multikinase and DNA-PK inhibitor combination immunomodulates melanomas, suppresses tumor progression, and enhances immunotherapies

Alexander K. Tsai, Asra Y. Khan, Christina E. Worgo, Lucy L. Wang, Yuanyuan Liang, Eduardo Davila

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)790-803
Number of pages14
JournalCancer immunology research
Volume5
Issue number9
DOIs
StatePublished - Sep 1 2017
Externally publishedYes

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Immunotherapy
Melanoma
T-Lymphocytes
DNA
Neoplasms
Melanoma-Specific Antigens
Phenotype
Therapeutics
Nerve Growth Factor Receptor
Tumor Microenvironment
T-Lymphocyte Subsets
Flow Cytometry
Cytokines
Ligands
regorafenib
Proteins
8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

Cite this

A multikinase and DNA-PK inhibitor combination immunomodulates melanomas, suppresses tumor progression, and enhances immunotherapies. / Tsai, Alexander K.; Khan, Asra Y.; Worgo, Christina E.; Wang, Lucy L.; Liang, Yuanyuan; Davila, Eduardo.

In: Cancer immunology research, Vol. 5, No. 9, 01.09.2017, p. 790-803.

Research output: Contribution to journalArticle

Tsai, Alexander K. ; Khan, Asra Y. ; Worgo, Christina E. ; Wang, Lucy L. ; Liang, Yuanyuan ; Davila, Eduardo. / A multikinase and DNA-PK inhibitor combination immunomodulates melanomas, suppresses tumor progression, and enhances immunotherapies. In: Cancer immunology research. 2017 ; Vol. 5, No. 9. pp. 790-803.
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