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

// Claudia Manzini 1 , Roberta Vene 2 , Irene Cossu 1 , Marina Gualco 3 , Simonetta Zupo 4 , Mariella Dono 4 , Francesco Spagnolo 5 , Paola Queirolo 5 , Lorenzo Moretta 7,* , Maria Cristina Mingari 8,9,10,* and Gabriella Pietra 8,9,* 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 7 IRCCS Ospedale Pediatrico Bambino Gesu, Roma, Italy; 8 Department of Experimental Medicine, University of Genoa, Genoa, Italy 9 Immunologia, IRCCS AOU San Martino-IST, Genoa, Italy 10 Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy * These authors share senior authorship Correspondence to: Lorenzo Moretta, email: // Gabriella Pietra, email: // Keywords : NK cells, melanoma, BRAF/MEK inhibitors, immunotherapy, cytokines, Immunology and Microbiology Section, Immune response, Immunity Received : April 19, 2016 Accepted : August 03, 2016 Published : August 22, 2016 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 BRAF V600 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.