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

Claudia Manzini1, Roberta Venè2, Irene Cossu1

  • 1IRCCS Istituto Giannina Gaslini, Genoa, Italy.

Oncotarget
|August 27, 2016
PubMed

Insights

BRAF and MEK inhibitors show potential for melanoma treatment. MEK inhibitors may impact natural killer (NK) cell function, but combinations with IL-15/IL-18 cytokines show promise for immunotherapy.

Area of Science:

  • Immunology
  • Oncology
  • Pharmacology

Background:

  • Targeted therapies for melanoma, including BRAF and MEK inhibitors, often lead to acquired resistance and tumor recurrence.
  • Combining BRAF/MEK inhibition with immunotherapy, particularly using natural killer (NK) cells, is a promising strategy for overcoming treatment limitations.
  • NK cells are crucial immune effectors in tumor immunotherapy due to their cytotoxic and regulatory functions.

Purpose of the Study:

  • To investigate the impact of BRAF and MEK inhibitors on the function of NK cells.
  • To evaluate the compatibility of these targeted therapies with NK cell-based immunotherapy, especially when combined with specific cytokines.
  • To provide a rationale for combining MEK inhibitors with cytokine-supported NK cell therapy in melanoma treatment protocols.

Main Methods:

  • Assessing the functional properties of NK cells cultured with IL-2 or IL-15 in the presence of BRAF inhibitor PLX4032 and MEK inhibitor PD0325901.
  • Analyzing the expression of activating NK receptors following treatment with PD0325901.
  • Evaluating the anti-tumor activity of NK cells exposed to IL-15/IL-18 and MEK inhibitors in vitro.
  • Testing the effect of PLX4032 and PD0325901 on pre-activated NK cells.

Main Results:

  • The BRAF inhibitor PLX4032 did not affect NK cell function when cultured with IL-2 or IL-15.
  • The MEK inhibitor PD0325901 reduced the expression of key activating NK receptors and impaired NK cell function.
  • PD0325901 did not inhibit the anti-tumor activity of NK cells activated by IL-15 and IL-18.
  • Neither PLX4032 nor PD0325901 inhibited IL-2 or IL-15 pre-activated NK cells.

Conclusions:

  • MEK inhibitors may modulate NK cell function, but their combination with IL-15/IL-18 cytokines warrants further investigation for melanoma immunotherapy.
  • BRAF and MEK inhibitors appear compatible with NK cell-based adoptive therapy, suggesting potential for combined treatment strategies.
  • These findings support the development of clinical protocols integrating cytokine-enhanced NK cell therapy with MEK inhibitors for melanoma patients.
Keywords:
BRAF/MEK inhibitorsImmune responseImmunityImmunology and Microbiology SectionNK cellscytokinesimmunotherapymelanoma

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