Abstract 3690: The leukocyte chemoattractant chemerin modulates PTEN via CMKLR1 in human tumors
Authors: Keith R. Rennier, Ping Wang, Robert Crowder, Russell K. Pachynski
Journal: Cancer Research (2017)

Abstract Background: Recent data in preclinical models has shown that phosphatase and tensin homolog (PTEN) loss correlated with decreased tumor immune cell infiltration as well as decreased response to T cell-based immunotherapy. Chemerin (RARRES2) is a recently identified endogenous leukocyte chemoattractant shown to recruit innate immune cells through its G-protein coupled receptor CMKLR1. Chemerin/RARRES2 is commonly downregulated in prostate and other cancers (e.g. sarcoma) compared to their normal tissue counterparts. Methylome-wide studies in multiple tumor types have identified RARRES2 as being one of the most hypermethylated genes, potentially leading to decreased chemerin expression. Our previous preclinical studies showed that forced overexpression of chemerin in tumors was capable of recruiting immune effector cells, including T cells, into the tumor microenvironment and suppressing tumor growth. Methods: In order to study the effects of chemerin overexpression on tumor cell intrinsic processes we exposed prostate and sarcoma tumor lines to exogenous recombinant chemerin in vitro. Evaluation of PTEN was performed at both the mRNA and protein levels, using both quantitative PCR and Western blotting, in comparison with normal prostate epithelia RWPE-1 as well as PTEN-null PC3 cells as controls. in vitro invasion assays were performed to investigate the functional impact of chemerin exposure on tumor intrinsic activity. Knockdown of CMKLR1 using siRNA was performed to determine its role in tumor response. Results: Using both prostate and sarcoma tumor lines, we found exogenous chemerin was able to significantly upregulate PTEN expression at both the mRNA and protein levels in a dose-response manner. Exposure to chemerin did not result in increased apoptosis or altered in vitro proliferation. Importantly, chemerin treatment significantly decreased in vitro tumor invasion. Knockdown studies showed CMKLR1 abrogation resulted in restored tumor migration, suggesting a link between this GPCR and PTEN expression and activity. Conclusions: For the first time, to our knowledge, we have shown a link between chemerin and PTEN expression and activity in both prostate and sarcoma tumor lines. Our collective study shows chemerin’s ability to upregulate PTEN activity and to mitigate tumor cell migration via CMKLR1. This work has functional implications on both tumor cell intrinsic and extrinsic responses to chemerin-based immunotherapeutic strategies. Further studies are needed to investigate the interaction between chemerin and PTEN signaling, and its connection to oncogenic signaling pathways manipulated in malignant tumors. Additionally, future in vivo studies using these tumor lines will help further elucidate the chemerin-PTEN axis and its role in tumor immunosurveillance. We hypothesize that increased chemerin-driven PTEN activity may help facilitate an improved immunotherapy response and functional ability to attack cancer cells. Citation Format: Keith R. Rennier, Ping Wang, Robert Crowder, Russell K. Pachynski. The leukocyte chemoattractant chemerin modulates PTEN via CMKLR1 in human tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3690. doi:10.1158/1538-7445.AM2017-3690