Melanoma cells suppress mast cell function via a melanin-dependent mechanism.

Mast cells (MCs) have a well-established detrimental role in allergic conditions, but they can also impact diverse malignant conditions, including melanoma. To study the latter, previous studies have mainly evaluated how MCs can influence melanomas/melanoma cells. However, the inverse scenario, that is, whether melanoma/melanoma cells might impact MCs, has received less attention. Here we investigated this issue and show that melanoma cell-conditioned medium had a strong growth-inhibitory impact on MCs, which was attributed to inhibition of MC proliferation combined with induction of apoptosis. Further, our data indicate that such effects were attributable to melanin present in the melanoma cell-conditioned medium, as similar antiproliferative effects were seen in response to both free melanin and to melanocores enriched from melanoma cell-conditioned medium. Melanin did not reduce the expression of MC markers but was shown to impair MC activation. We also demonstrate that melanin is taken up by MCs, both in cultured MCs and in vivo in melanoma tumors, and it was observed that melanin, after uptake, can be found in the MC nucleus. Further, we show that melanin had marked effects on the nuclear morphology in MCs accompanied by clipping of core histone 3, and it is demonstrated that these events were dependent on translocation of tryptase, a granule-localized protease, into the MC nucleus. Tryptase was also shown to affect the mechanism of melanin-induced cell death. Altogether, the present study outlines a newly identified mechanism by which melanoma cells can suppress MC function, potentially representing an immunosuppressive mechanism that may influence tumor growth.