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

Abstract

Summary 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.

Expression of Bioactive Chemerin by Keratinocytes Inhibits Late Stages of Tumor Development in a Chemical Model of Skin Carcinogenesis

“…Provided the well-established role of the chemerin-ChemR23 system in the recruitment of some of these cell populations, including NK cells, macrophages and dendritic cells (2, 3, 11, 52), these leukocytes might contribute to the observed anti-tumoral properties of chemerin. Previous reports attributed the anti-tumoral effects of chemerin to the recruitment of NK cells (37, 53). In our model, no significant differences in leukocyte populations were observed in the skin of mice in basal conditions (Figures 3D,E), but also at different time points of the DMBA-TPA procedures (not shown), including for the specific leukocyte populations known to be recruited by chemerin, such as NK cells.…”

D-α-Tocopherol-Based Micelles for Successful Encapsulation of Retinoic Acid

“…[ 1 , 2 ]. Recently it was demonstrated that a topical application of ATRA could inhibit melanoma growth, not only by exerting a differentiating effect, but also by influencing tumor immunity by up-regulation of chemerin, which in turn enhances Chemochine Like Receptor-1 (CMKLR-1)-expressing natural killer cell infiltration, creating an immunosuppressive tumor environment [ 3 , 4 ]. Although melanoma represents only 4% of skin cancers, because of its high aggressive behavior and poor prognosis, it is responsible for 80% of deaths related to dermatological cancers [ 5 ].…”

Dietary Derived Micronutrients Modulate Immune Responses Through Innate Lymphoid Cells

“…Recently, a work from Song and collaborators showed that atRA recruits NK cells to infiltrate tumors and exert their cytotoxic function in a melanoma mouse model ( 32 ). Likewise, atRA improves the lytic activity of the antitumor agent, anti-CD38 monoclonal antibody, against multiple myeloma cells ( 33 ).…”