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Chemerin Reactivates PTEN and Suppresses PD-L1 in Tumor Cells

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Chemerin Reactivates PTEN and Suppresses PD-L1 in Tumor Cells Published OnlineFirst June 30, 2020; DOI: 10.1158/1078-0432.CCR-19-4245 CLINICAL CANCER RESEARCH | TRANSLATIONAL CANCER MECHANISMS AND THERAPY Chemerin Reactivates PTEN and Suppresses PD-L1 in Tumor Cells via Modulation of a Novel CMKLR1-mediated Signaling Cascade A C Keith Rennier1, Woo Jae Shin1, Ethan Krug1, Gurpal Virdi1, and Russell K. Pachynski1,2,3 ABSTRACT ◥ Purpose: Chemerin (retinoic acid receptor responder 2, Results: We show for the first time that human tumors exposed RARRES2) is an endogenous leukocyte chemoattractant that to exogenous chemerin significantly upregulate PTEN expression/ recruits innate immune cells through its receptor, ChemR23. activity, and concomitantly suppress programmed death ligand-1 RARRES2 is widely expressed in nonhematopoietic tissues and (PD-L1) expression. CMKLR1 knockdown abrogated chemerin- often downregulated across multiple tumor types compared with induced PTEN and PD-L1 modulation, exposing a novel CMKLR1/ normal tissue. Recent studies show that augmenting chemerin in the PTEN/PD-L1 signaling cascade. Targeted inhibitors suggested sig- tumor microenvironment significantly suppresses tumor growth, in naling was occurring through the PI3K/AKT/mTOR pathway. part, by immune effector cells recruitment. However, as tumor cells Chemerin treatment significantly reduced tumor migration, while express functional chemokine/chemoattractant receptors that significantly increasing T-cell–mediated cytotoxicity. Chemerin impact their phenotype, we hypothesized that chemerin may have treatment was as effective as both PD-L1 knockdown and the additional, tumor-intrinsic effects. anti–PD-L1 antibody, atezolizumab, in augmenting T-cell– Experimental Design: We investigated the effect of exogenous mediated tumor lysis. Forced expression of chemerin in human chemerin on human prostate and sarcoma tumor lines. Key sig- DU145 tumors significantly suppressed in vivo tumor growth, and naling pathway components were elucidated using qPCR, Western significantly increased PTEN and decreased PD-L1 expression. blotting, siRNA knockdown, and specific inhibitors. Functional Conclusions: Collectively, our data show a novel link between consequences of chemerin treatment were evaluated using chemerin, PTEN, and PD-L1 in human tumor lines, which may in vitro and in vivo studies. have a role in improving T-cell–mediated immunotherapies. Introduction Chemerin/RARRES2 is commonly downregulated across several tumor types, including melanoma, breast, prostate, and sarcoma, Chemerin, or RARRES2 (retinoic acid receptor responder 2), is an compared with their normal tissue counterparts (1). Our group was endogenous leukocyte chemoattractant but has myriad roles in adi- the first to show that forcible reexpression of chemerin in the tumor pogenesis, metabolism, angiogenesis, microbial defense, and cancer. microenvironment (TME) resulted in recruitment and increased Chemerin is widely expressed in nonhematopoietic tissues, with low/ tumor-infiltrating effector leukocytes, leading to a significant reduc- no expression noted in leukocytes (1). Chemerin recruits innate tion in the growth of aggressive B16 melanoma in a mouse model (10). immune cells along its concentration gradient to sites of inflammation While recruitment of immune effector cells is important, tumor cell– via its G protein–coupled receptor (GPCR) chemokine-like receptor-1 intrinsic oncogenic signaling pathways can also impact directed (CMKLR1, also known as ChemR23; refs. 2, 3). In humans, CMKLR1 immune responses, and thus play a key role in determining therapeutic expression on leukocytes has been shown in macrophages, dendritic efficacy. cells (DCs), and natural killer (NK) cells with comparable expression in PTEN (PTEN deleted on chromosome 10) is a critical tumor the mouse (3–6). While data are limited, CMKLR1 expression has been suppressor whose expression is downregulated and/or lost in many detected on human tumor cells (7, 8), suggesting that interaction with tumor types (11). PTEN loss has been correlated with activation of the its endogenous ligand chemerin may modulate tumor cell phenotype, PI3K–AKT pathway, which is implicated in the pathogenesis of these as seen with other chemokine/receptor pairs (9). cancers, and is particularly relevant in prostate cancer (12). Deleterious PTEN alterations are found in up to approximately 20%–30% of primary prostate cancer tissues and in approximately 40%–60% of 1 Division of Oncology, John T. Milliken Department of Medicine, Washington metastatic tissues, and are among the most common genomic events in 2 University School of Medicine, St. Louis, Missouri. Alvin J. Siteman Cancer prostate cancer (13). While less commonly mutated in sarcoma, PTEN Center, Washington University School of Medicine, St. Louis, Missouri. 3The Bursky Center for Human Immunology & Immunotherapy Programs (CHiiPs), downregulation has also been shown to play an important role in a Washington University School of Medicine, St. Louis, Missouri. subset of soft-tissue sarcomas (STS), with one study showing 57% of STSs with decreased PTEN expression (14). Furthermore, aberrations Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). in the downstream PI3K/Akt pathway are almost always implicated in the pathogenesis of sarcomas, with essentially 100% of advanced-stage Corresponding Author: Russell K. Pachynski, Washington University in St. Louis osteosarcomas showing dysregulation in this pathway (15). School of Medicine, 660 S Euclid Ave, St Louis, MO 63110. Phone: 314-286-2341; – E-mail: [email protected] Here, we examine the effects of chemerin on tumor cell intrinsic phenotype and describe, for the first time, the ability of chemerin to Clin Cancer Res 2020;XX:XX–XX upregulate the expression and function of PTEN in human prostate doi: 10.1158/1078-0432.CCR-19-4245 and sarcoma tumor cell lines. Importantly, we show, also for the first Ó2020 American Association for Cancer Research. time, that chemerin treatment of tumor cells results in a concomitant AACRJournals.org | OF1 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst June 30, 2020; DOI: 10.1158/1078-0432.CCR-19-4245 Rennier et al. nmol/L) was used for complete inhibition for 24 hours. PI3k inhibitor Translational Relevance (BEZ235, Selleck Chemical, 100 nmol/L) was used for 24 hours Loss of the tumor suppressor PTEN in human cancers has pretreatment. recently been shown to contribute to resistance to immunotherapy; unfortunately, therapeutic reactivation of PTEN has remained siRNA transfection elusive. Chemerin (retinoic acid receptor responder 2, RARRES2) X-tremegene siRNA Transfection Reagent (No. 4476093001, is a leukocyte chemoattractant known to recruit effector immune Roche) and each siRNA was added drop-wise to the cell media. cells, and is often downregulated in tumors. Recent data links siRNAs (CMKLR1, PTEN, and PD-L1) were all 10-mmol/L stock chemerin to PTEN expression, and thus we hypothesized that concentration. The optimal ratio of transfection reagent to siRNA chemerin may act to augment PTEN and result in improved (4:10) gave a final concentration of 40 pmol/L, and signal knockdown responses to immunotherapy. Herein, we describe a novel pathway was evaluated via Western blot analysis (Supplementary Figs. S1 and in human tumors whereby chemerin, through its G protein– S8). ChemR23/CMKLR1 (sc-44633, Santa Cruz Biotechnology), PD- coupled receptor CMKRL1, induces PTEN expression and activity, L1 (sc-39699, Santa Cruz Biotechnology), PTEN (6251S, Cell Signaling while concurrently suppresses programmed death ligand-1 (PD- Technology), and Control (sc-37007, Santa Cruz Biotechnology) L1) expression. We show that chemerin treatment significantly siRNA were used for signal knockdown. The control siRNA-A is a inhibits tumor migration/invasion, increases T-cell–mediated nonspecific scrambled sequence used as a negative control in the cytotoxicity, and suppresses in vivo tumor growth. Taken together, siRNA-targeted knockdown experiments. these results identify chemerin as a promising clinical therapeutic able to reactivate PTEN and suppress PD-L1 expression, thus Flow cytometry potentially improving responses to immunotherapy. Cells were stained with the target-specific antibody (Supplementary Table S1) as labeled in each figure at 1 mL/1 Â 105 cells for 30 minutes at 4C. Cells were analyzed using a FACSCalibur (BD Biosciences). downregulation of programmed death ligand-1 (PD-L1) expression, Real-time RT-PCR which directly translates into significantly increased T-cell– Sample RNA was isolated using TRizol (Invitrogen) and RNeasy mediated cytotoxicity. These effects were dependent on CMKLR1, Mini RNA Isolation Kit (Qiagen). RNA concentrations were verified as siRNA knockdown and specific inhibition with the CMKLR1 using NanoDrop 2000 (Thermo Fisher Scientific). Bio-Rad iScript antagonist, a-NETA, completely abrogated these effects. In vivo Advanced cDNA Synthesis Kit converted RNA to cDNA via the studies using the human DU145 prostate tumor line show that manufacturer’s protocol. cDNA was amplified with iTaq Universal expression of chemerin in the TME significantly suppresses tumor SYBR Green Supermix (Bio-Rad) via the manufacturer’s protocol. A growth, increasing tumor PTEN and decreasing tumor PD-L1 CFX96 Real-Time PCR System (Bio-Rad) was used to quantify gene C expression compared with controls. Collectively, these studies
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