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

May 8, 2019Immunology

Chemerin helps all-trans retinoic acid slow tumors by attracting natural killer cells through CMKLR1

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Abstract

Loss of chemerin expression is associated with aggravated tumor growth in melanoma.

Chemerin is normally expressed in the skin but is down-regulated during melanoma progression.
Mice lacking chemerin exhibited increased melanoma growth and reduced natural killer (NK) cells in tumors.
Topical application of all-trans retinoic acid (atRA) increased chemerin levels in the skin, primarily from dermal cells.
atRA treatment also significantly boosted NK cell presence in tumors, which was dependent on chemerin and its receptor CMKLR1.
Lack of CMKLR1 partially negated the anti-tumor effects of atRA, suggesting it plays a role in NK cell recruitment.

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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. Rarres2mice, 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 Rarres2mice and Cmklr1mice, suggesting a dependency of NK cell recruitment on the chemerin-CMKLR1 axis in melanoma. Despite comparable melanoma growth detected in wild-type mice and Cmklr1mice, 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 Cmklr1mice 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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Chemerin partly mediates tumor‐inhibitory effect of all‐trans retinoic acid via CMKLR1‐dependent natural killer cell recruitment

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