Chemerin partly mediates tumor‐inhibitory effect of all‐ trans retinoic acid via CMKLR 1‐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 (at RA ) is a potent inducer of chemerin, and we previously reported that at RA 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 at RA . 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 CMKLR 1, the functional receptor of chemerin. Topical treatment with at RA up‐regulated skin chemerin expression, which was primarily derived from dermal cells. Moreover, at RA 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– CMKLR 1 axis in melanoma. Despite comparable melanoma growth detected in wild‐type mice and Cmklr1 −/− mice, lack of CMKLR 1 partially abrogated the melanoma‐inhibitory effect of at RA . This may be due to the inability to enhance tumor‐infiltrating NK cells in Cmklr1 −/− mice following at RA 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 at RA by up‐regulating chemerin to enhance CMKLR 1‐dependent NK cell recruitment.