Chemerin Reactivates PTEN and Suppresses PD-L1 in Tumor Cells via Modulation of a Novel CMKLR1-mediated Signaling Cascade

Abstract

Purpose: Chemerin (retinoic acid receptor responder 2, RARRES2) is an endogenous leukocyte chemoattractant that recruits innate immune cells through its receptor, ChemR23. RARRES2 is widely expressed in nonhematopoietic tissues and often downregulated across multiple tumor types compared with normal tissue. Recent studies show that augmenting chemerin in the tumor microenvironment significantly suppresses tumor growth, in part, by immune effector cells recruitment. However, as tumor cells express functional chemokine/chemoattractant receptors that impact their phenotype, we hypothesized that chemerin may have additional, tumor-intrinsic effects. Experimental Design: We investigated the effect of exogenous chemerin on human prostate and sarcoma tumor lines. Key signaling pathway components were elucidated using qPCR, Western blotting, siRNA knockdown, and specific inhibitors. Functional consequences of chemerin treatment were evaluated using in vitro and in vivo studies. Results: We show for the first time that human tumors exposed to exogenous chemerin significantly upregulate PTEN expression/ activity, and concomitantly suppress programmed death ligand-1 (PD-L1) expression. CMKLR1 knockdown abrogated chemerininduced PTEN and PD-L1 modulation, exposing a novel CMKLR1/ PTEN/PD-L1 signaling cascade. Targeted inhibitors suggested signaling was occurring through the PI3K/AKT/mTOR pathway. Chemerin treatment significantly reduced tumor migration, while significantly increasing T-cell-mediated cytotoxicity. Chemerin treatment was as effective as both PD-L1 knockdown and the anti-PD-L1 antibody, atezolizumab, in augmenting T-cellmediated tumor lysis. Forced expression of chemerin in human DU145 tumors significantly suppressed in vivo tumor growth, and significantly increased PTEN and decreased PD-L1 expression. Conclusions: Collectively, our data show a novel link between chemerin, PTEN, and PD-L1 in human tumor lines, which may have a role in improving T-cell-mediated immunotherapies.

Mechanical Loading-Driven Tumor Suppression Is Mediated by Lrp5-Dependent and Independent Mechanisms

“…The protein array analysis for cytokines and chemokines revealed that the levels of chemerin and nexin were mainly altered by knee loading in the serum of wild-type and knockout mice, as well as the responses to dopamine and cholesterol in tumor cells. It is reported that chemerin suppresses hepatocellular carcinoma metastasis, breast cancer growth, prostate cancer progression, skin carcinogenesis, and melanoma [ 36 , 37 , 38 , 39 , 40 ], while nexin is a stimulator of peritoneal metastasis in ovarian cancer [ 41 ], as well as the growth, migration, and invasion of breast cancer cells [ 42 ]. It is also reported that Wnt signaling in tumor cells is inhibited by chemerin while nexin is a downstream target of Wnt signaling [ 43 , 44 , 45 ].…”

Identification of Metabolism-Associated Prostate Cancer Subtypes and Construction of a Prognostic Risk Model

“…TME is a remarkable factor impacting the occurrence and development of PCa. Many cancer-promoting factors play a role in the EMT pathway (43). For instance, the expression of PDL1 can affect the prognosis of adrenocortical carcinoma (44).…”

Chemerin Signaling in Cancer

“…Programmed death ligand 1 (PD-L1) is commonly upregulated on tumors and blocks the activity of T-cells. As a consequence of PTEN reactivation, PD-L1 was suppressed and T-cell cytotoxicity was enhanced by chemerin [ 17 ]. Both of these studies described higher PTEN protein levels upon chemerin overexpression or supplementation of exogenous chemerin [ 14 , 17 ].…”

“…As a consequence of PTEN reactivation, PD-L1 was suppressed and T-cell cytotoxicity was enhanced by chemerin [ 17 ]. Both of these studies described higher PTEN protein levels upon chemerin overexpression or supplementation of exogenous chemerin [ 14 , 17 ]. In prostate cells, PTEN mRNA was also induced [ 17 ].…”

“…Both of these studies described higher PTEN protein levels upon chemerin overexpression or supplementation of exogenous chemerin [ 14 , 17 ]. In prostate cells, PTEN mRNA was also induced [ 17 ]. Whether chemerin upregulates PTEN expression and in addition destabilized the CMKLR1/PTEN complex in both tumor cell types needs further studies.…”