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Oncotarget. 2016 Sep 20;7(38):60858-60871. doi: 10.18632/oncotarget.11504.

Cytokines can counteract the inhibitory effect of MEK-i on NK-cell function.

Author information

1
IRCCS Istituto Giannina Gaslini, Genoa, Italy.
2
Oncologia Molecolare e Angiogenesi, IRCCS AOU San Martino-IST, Genoa, Italy.
3
Anatomia Patologica, IRCCS AOU San Martino-IST, Genoa, Italy.
4
Diagnostica Molecolare, IRCCS AOU San Martino-IST, Genoa, Italy.
5
Oncologia Medica 2, IRCCS AOU San Martino-IST, Genoa, Italy.
6
Department of Experimental Medicine, University of Genoa, Genoa, Italy.
7
Immunologia, IRCCS AOU San Martino-IST, Genoa, Italy.
8
Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy.

Abstract

Oncogene-targeted therapies based on mutated BRAF- and/or MEK-specific inhibitors have been developed for melanoma treatment. Although these drugs induce tumor regression in a high percentage of patients, clinical responses are frequently limited in time and tumors often recur. Recent studies suggested that the combination of BRAF/MEK inhibition with immunotherapy could represent a promising strategy for the cure of melanoma. NK cells are suitable effectors for tumor immunotherapy. Here we show that PLX4032 (a mutant BRAFV600 inhibitor) had no effect on the functional properties of NK cells cultured in the presence of IL-2 or IL-15. In contrast, PD0325901 (a MEK inhibitor) induced the down-regulation of the main activating NK receptors and inhibited NK cell function. Importantly, PD0325901 did not affect the anti-tumor activity of NK cells that had been exposed to a combination of IL-15 and IL-18. In addition, both PLX4032 and PD0325901 did not exert any inhibitory effect on in vitro IL-2 or IL-15 pre-activated NK cells.Our data may provide a rationale for future clinical protocols that combine IL-15/IL-18 cytokine administration with MEK inhibitors. In addition, they suggest that oncogene-targeting drugs are compatible with NK-based adoptive therapy.

KEYWORDS:

BRAF/MEK inhibitors; Immune response; Immunity; Immunology and Microbiology Section; NK cells; cytokines; immunotherapy; melanoma

PMID:
27563819
PMCID:
PMC5308621
DOI:
10.18632/oncotarget.11504
[Indexed for MEDLINE]
Free PMC Article

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