Chemerin [RARRES2 [retinoic acid receptor responder 2], TIG2 [tazarotene induced gene 2 (TIG2)]] is a multifunctional cytokine initially described in skin cultures upon exposure to the synthetic retinoid tazarotene. Its secreted pro-form, prochemerin, is widely expressed, found systemically, and is readily converted into active chemerin by various proteases. Subsequent studies elucidated major roles of chemerin as both a leukocyte chemoattractant as well as an adipokine. Chemerin's main chemotactic receptor, the G-protein coupled receptor CMKLR1, is expressed on macrophages, dendritic, and NK cells. With respect to its role in immunology, chemerin mediates trafficking of these cells to sites of inflammation along its concentration gradient, and likely helps coordinate early responses, as it has been shown to have antimicrobial and angiogenic properties, as well. Recently, there has been mounting evidence that chemerin is an important factor in various cancers. As with its role in immune responses—where it can act as both a pro- and anti-inflammatory mediator—the potential functions or correlations chemerin has in or with cancer appears to be context dependent. Most studies, however, suggest a downregulation or loss of chemerin/RARRES2 in malignancies compared to the normal tissue counterparts. Here, we perform a comprehensive review of the literature to date and summarize relevant findings in order to better define the roles of chemerin in the setting of the tumor microenvironment and tumor immune responses, with an ultimate focus on the potential for therapeutic intervention.

Infiltration of immune cells into the tumor microenvironment (TME) can regulate growth and survival of neoplastic cells, impacting tumorigenesis and tumor progression. Correlations between the number of effector immune cells present in a tumor and clinical outcomes in many human tumors, including breast, have been widely described. Current immunotherapies utilizing checkpoint inhibitors or co-stimulatory molecule agonists aim to activate effector immune cells. However, tumors often lack adequate effector cell numbers within the TME, resulting in suboptimal responses to these agents. Chemerin ( RARRES2 ) is a leukocyte chemoattractant widely expressed in many tissues and is known to recruit innate leukocytes. CMKLR1 is a chemotactic cellular receptor for chemerin and is expressed on subsets of dendritic cells, NK cells, and macrophages. We have previously shown that chemerin acts as a tumor suppressive cytokine in mouse melanoma models by recruiting innate immune defenses into the TME. Chemerin/ RARRES2 is down-regulated in many tumors, including breast, compared to normal tissue counterparts. Here, using a syngeneic orthotopic EMT6 breast carcinoma model, we show that forced overexpression of chemerin by tumor cells results in significant recruitment of NK cells and T cells within the TME. While chemerin secretion by EMT6 cells did not alter their phenotypic behavior in vitro , it did significantly suppress tumor growth in vivo . To define the cellular effectors required for this anti-tumor phenotype, we depleted NK cells or CD8+ T cells and found that either cell type is required for chemerin-dependent suppression of EMT6 tumor growth. Finally, we show significantly reduced levels of RARRES2 mRNA in human breast cancer samples compared to matched normal tissues. Thus, for the first time we have shown that increasing chemerin expression within the breast carcinoma TME can suppress growth by recruitment of NK and T cells, thereby supporting this approach as a promising immunotherapeutic strategy.

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.

Renal cell carcinoma (RCC) comprises 4.2% of all new cancer cases in the United States and 30% of cases are metastatic (mRCC) at diagnosis. Brain metastatic RCC historically has poor prognosis, but the development of immune checkpoint inhibitors has revolutionized their care and may be successfully combined with SBRT to improve prognosis. Here, we present a case of a patient with mRCC who had brain metastases treated with concurrent immune checkpoint inhibitors and SBRT. He continues to survive with good functional status years following his initial diagnosis. We discuss the relevant history regarding treatment approach in patients with brain metastatic RCC, ongoing trials focusing on the combination of immunotherapy and radiation, and the potential and promise of the abscopal effect.

<div>AbstractPurpose:<p>Chemerin (retinoic acid receptor responder 2, <i>RARRES2</i>) is an endogenous leukocyte chemoattractant that recruits innate immune cells through its receptor, ChemR23. <i>RARRES2</i> 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.</p>Experimental Design:<p>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 <i>in vitro</i> and <i>in vivo</i> studies.</p>Results:<p>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 chemerin-induced 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-cell–mediated tumor lysis. Forced expression of chemerin in human DU145 tumors significantly suppressed <i>in vivo</i> tumor growth, and significantly increased PTEN and decreased PD-L1 expression.</p>Conclusions:<p>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.</p></div>