Chemerin partly mediates tumor-inhibitory effect of all-trans retinoic acid via CMKLR1-dependent natural killer cell recruitment.

Down-regulated chemerin expression has been reported to correlate with poor prognosis of several types of cancer including melanoma. All-trans retinoic acid (atRA) is a potent inducer of chemerin, and we previously reported that atRA inhibited murine melanoma growth through enhancement of anti-tumor T-cell immunity. Here, we aimed to investigate whether loss of endogenous chemerin accelerated melanoma growth and whether chemerin was involved in the melanoma-inhibitory effect of atRA. We demonstrated that chemerin was constitutively expressed in the skin, which was down-regulated during murine melanoma growth. Rarres2^-/- mice, which are deficient in chemerin, exhibited aggravated tumor growth and impaired tumor-infiltrating natural killer (NK) cells that express CMKLR1, the functional receptor of chemerin. Topical treatment with atRA up-regulated skin chemerin expression, which was primarily derived from dermal cells. Moreover, atRA treatment significantly enhanced tumor-infiltrating NK cells, which was completely abrogated in Rarres2^-/- mice and Cmklr1^-/- mice, suggesting a dependency of NK cell recruitment on the chemerin-CMKLR1 axis in melanoma. Despite comparable melanoma growth detected in wild-type mice and Cmklr1^-/- mice, lack of CMKLR1 partially abrogated the melanoma-inhibitory effect of atRA. This may be due to the inability to enhance tumor-infiltrating NK cells in Cmklr1^-/- mice following atRA treatment. Collectively, our study suggests that down-regulation of chemerin could be a strategy used by cancers such as melanoma to impair anti-tumor NK cell immunity and identifies a new anti-tumor mechanism of atRA by up-regulating chemerin to enhance CMKLR1-dependent NK cell recruitment.

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