Chemokines sound the alarmin: The role of atypical chemokine in inflammation and cancer

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Chemokines sound the alarmin: The role of atypical chemokine in inflammation and cancer Elena Monica Borronia,b, Benedetta Savinoa,b, Raffaella Bonecchia,c, Massimo Locatia,b,

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a

Humanitas Clinical and Research Center, Via Manzoni 113, I-20089 Rozzano, Italy Department of Medical Biotechnologies and Translational Medicine, Università degli Studi di Milano, Via fratelli Cervi, I-20090 Segrate, Italy c Department of Biomedical Sciences, Humanitas University, via Rita Levi Montalcini 4, I-20089 Pieve Emanuele, Italy b

A R T I C LE I N FO

A B S T R A C T

Keywords: Chemokines Scavenger receptors Atypical chemokine receptors Cancer related inflammation

As main drivers of leukocyte recruitment during inflammatory reactions, chemokines act as mediatrs of alarmins in priming host defense responses after tissue exposure to toxic or infectious agents, immunomediated damage, and in inflammation-driven tumors. Chemokines can therefore be considered alarm signals generated by tissues in a broad number of conditions, and mechanisms controlling chemokines biological activities are therefore key to regulate tissue reactions induced by alarmins. By transporting, presenting or scavenging different sets of chemokines, atypical chemokine receptors represent an emerign subfamily of chemokine receptors which operates in tissues as chemokine gatekeepers in order to establish and shape their gradients and coordinate leukocyte recruitment.

1. Introduction When exposed to different types of agents perturbing homeostasis, vascularized tissues react by activating a stereotyped process called inflammation. Vascular permeability and adhesiveness are increased allowing circulating leukocytes to access the subendothelial space and finally their entrance and activation in the inflamed tissue. A number of soluble mediators are implicated in the tight coordination of this process. Among these, a large family of chemoattractant cytokines name chemokines (from chemotactic cytokines) for their main role in selecting the appropriate leukocyte subset to be recruited and in directing them in their directional migration in the tissue, finally resulting in their accumulation and activation in response to the causing agent [1]. The chemokine system is a complex network including over 50 ligands and 25 receptors. Beyond their chemotactic activity, ligands share a conserved protein structure called “chemokine scaffold”, which is based on two cysteine residues located at the far end of the aminoterminus of the protein. The relative positioning of these cysteine residues identifies two main subfamilies (CC and CXC chemokines, which have the cysteine residues adjacent or separated by a single intervening amino acid, respectively) and two minor subfamilies (C and CX3C, with have a single cysteine residue in the amino-terminus or with three residues separating the cysteine tandem, respectively). This structurebased chemokine classification is reflected in the classification of their

receptors. The chemokine receptors family includes 10 receptors recognizing CC chemokines (CCR1 to 10) and 6 recognizing CXC chemokines (CXCR1 to 6), plus 2 receptors (XCR1 and CX3CR1) recognizing the only known C and CX3C chemokine known, respectively [2]. These 18 receptors represent a distinct subfamily of the G proteincoupled receptors (GPCR) superfamily and all share the ability to trigger a Gαi-mediated signaling pathway inducing directional cell movement along the ligand gradient [3]. Being chemokines direct mediators of leukocyte infiltration during inflammatory reactions, mechanisms controlling their biological activities are key to regulate tissue reactions induced by alarmins. A first mechanism is represented by the tight control of chemokine expression, particularly for “inflammatory” chemokines, which are only produced in response to inflammatory and immune stimuli, while “homeostatic” chemokines control leukocyte homing and lymphocyte recirculation in normal conditions [4]. Chemokines are also targets of post-translational modifications that influence their functional properties, including processing at the amino- and carboxyl-termini by proteases and modifications such as nitration and citrullination [5,6]. We will here focus on the non-redundant role in the control of the chemokine system played by a distinct group of “atypical” chemokine receptors [7], which control the chemokine system by shaping chemokine distribution (concentration and gradient) in tissues by means of clearance and transport mechanisms [8].

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Corresponding author at: Humanitas Clinical and Research Center, Via Manzoni 113, 20089 Rozzano, Italy. E-mail addresses: [email protected] (E.M. Borroni), [email protected] (B. Savino), raff[email protected] (R. Bonecchi), [email protected] (M. Locati). https://doi.org/10.1016/j.smim.2018.10.005 Received 23 August 2018; Accepted 8 October 2018 1044-5323/ © 2018 Published by Elsevier Ltd.

Please cite this article as: Borroni, E.M., Seminars in Immunology, https://doi.org/10.1016/j.smim.2018.10.005

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Fig. 1. ACKRs: tissue distribution, ligand specificity, and biological functions. ACKRs recognize chemokines and control their distribution in tissues, thus operating as a prominent regulatory mechanisms of the chemokine system. Chemokines are color-coded as pro-inflammatory (red), homeostatic (green) and those with mixed function (yellow). Non-chemokine ligands and reported in grey.

2. Structural and functional properties of ACKRs

2.2. Ligands

As mentioned, conventional chemokine receptors represent a wellcharacterized GPCR subfamily able to directly induce leukocyte migration. More recently, a distinct subfamily of chemokine receptors involved in the fine-tuning chemokine-based responses in both homeostatic and inflammatory contexts has been recognized. These are referred to as “atypical” chemokine receptors (ACKRs) as specific structural determinants cause either their apparent inability to signal or their ability to use alternative signalling pathways to those seen with the conventional receptors [8,9]. This receptor subfamily includes at present four accepted members (ACKR1, formerly known as Duffy Antigen for Chemokines or DARC [10]; ACKR2, formerly known as D6 [11,12]; ACKR3, formerly known as CXCR7 [13]; ACKR4, formerly known as CCRL1 or CCXCKR [14]), plus a fifth member for which evidence are still not conclusive (ACKR5) [2] (Fig. 1).

Consistent with their regulatory activity on a highly promiscuous system, all ACKRs recognizes more than one ligand, and some show a remarkably broad number of ligands, such as in case of ACKR1 and ACKR2 [33]. Again at variance with conventional chemokine receptors, ACKRs binding specificity may not be restricted by the structural properties of the ligand, so that some ACKRs are selective for CC or CXC chemokines (ACKR2 and ACKR3, which are restricted to CC and CXC chemokines, respectively), but other promiscuous receptors cross this boundary and recognize ligands of different subfamilies (ACKR1 and ACKR4). Finally, ACKRs also recognize viral chemokines, as for vCCL2/ vMIP-II which acts as a ligand for ACKR3 [34], and in some cases function as pathogen coreceptors (ACKR2 as HIV-1/HIV-2 coreceptor on astrocytes [35]; ACKR1 as cell receptor for Plasmodium vivax and knowlesi [36,37]). Besides chemokines, ACKR recognition of chemotatic peptides has also been observed. In particular, ACKR3 binds the pleiotropic cytokine with chemokine-like functions Macrophage Migration-Inhibitory Factor [38], as well as adrenomedullin and the intermediate opioid peptide BAM22 [39,40], and ACKR5 binds the chemoattractant chemerin [41]. This evidence indicates that ACKRs exert control on leukocyte chemoattraction beyond the chemokine system borders.

2.1. Expression pattern Though ACKRs have been reported in some leukocyte subsets, including hematopoietic progenitors, B and T lymphocytes and alveolar macrophages, as well as erythrocytes, differently from their conventional counterparts ACKRs are usually poorly expressed within the hematopoietic compartment. Conversely, ACKRs are usually expressed at barrier tissues (i.e. skin, lung, gut and placenta; ACKR2 [15]) and on stromal cells (ACKR4 [16];), as well as vascular (ACKR1 [17], ACKR3 [18], ACKR5 [19]) and lymphatic (ACKR2 [20], ACKR4 [21]) endothelial cells. In some cases they may display distinct functions depending upon their expression profile, as exemplified by ACKR1 that acts as a chemokine sink on erythrocytes and as a chemokine transporter on endothelial cells [22], but in general their expression profile is well in line with key function of chemokine gradient remodelers. Emerging evidence clearly indicates that, besides tumor microenvironment cells, ACKRs expression also occurs directly on cancer cells. As examples, ACKR2 expression has been reported on Kaposi sarcoma spindle cells, breast and cervical carcinoma [23–25], and ACKR5 is expressed on human high grade glioblastoma and breast cancer cells [26–28]. Similarly, ACKRs expression has also been reported in hematological malignancies, such as diffuse large B cell lymphoma and chronic lymphocytic leukemia cells [29,30], and acute lymphoid and myeloid leukemia cells [31,32].

2.3. Structure As a consequence of the growing interest on the role of ACKRs in a variety of in vivo contexts, information on the structure/function relationship regulating their chemokine binding properties has recently became available. Regions involved in ligand binding in conventional chemokine receptors include the N terminus and, in particular, a sulfated tyrosine motif in this domain [42]. This structural determinant is also maintained within the ACKR subfamily and appears to be equally relevant as, for example, a conserved sulfated tyrosine residue in the Nterminus of ACKR2 is essential for ligand internalization. Of note, a sulfated peptide derived from this region is capable of binding inflammatory chemokines and to inhibit their interaction with their cognate conventional receptors [43], opening new perspectives into pharmacological targeting of the chemokine system mutated by ACKRs. While ACKRs seem to share with conventional receptors structural determinants for ligand binding, they show alterations in highly conserved structural determinants in TM domains involved in “micro2

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switch” elements required for chemokine receptors activation [44]. According to this, ACKRs are actually classified as “not DRY” receptors, as they either lack the DRY in TM3 (ACKR1, ACKR5) or exhibit significant modifications in the DRYLAIV consensus (ACKR2, ACKR3, ACKR4) [45]. ACKRs also display modifications on an highly conserved site located in TM3/ILC2 which is important for the selectivity of receptor/G protein interaction and the efficiency of G protein activation [45,46]. These structural variants account for the functional differences in the signaling pathways of the two chemokine receptor families [46]. Besides TM regions, ACKRs also display an intracytoplasmatic Cterminal domain particularly rich of Ser/Thr clusters, involved in direct physical interaction with β-arrestins, which critically impact on their constitutive and ligand-induced β-arrestins coupling properties [47]. Interestingly, although the role of Ser/Thr residues phosphorylation is still debated [48,49], these residues are well conserved across species, further supporting their potential role in regulating ACKRs signaling properties and biological functions [45]. 2.4. Signaling and trafficking properties Fig. 2. Role of ACKR as regulators of tissue response to alarmins. Chemokines can be viewed as alarm signals generated in response to alarmins released by stressed tissues. By acting at conventional chemokine receptors expressed on different leukocytes subsets, chemokine coordinate their recruitment and activation and promote inflammation. When expressed on the same leukocyte target, atypical chemokine receptors may control its activation by interfering with conventional chemokine receptors’ signalling. Atypical chemokine receptors expressed on endothelial cells and other non-leukocyte cells also tune chemokine concentrations by transporting or degrading them.

GPCR are currently thought to signal through G protein and β-arrestin modules in balanced fashion [50]. Under specific conditions several GPCR, including chemokine receptors, may adopt different G protein or β-arrestin signaling properties and operate as biased receptors [50,51]. A common feature of ACKRs is their intrinsic inability to promote cell migration as a consequence of their negligible signaling activity via G protein-dependent signaling pathways [52–55]. While structure/activity properties responsible for impaired G protein coupling and signaling properties of ACKRs deserve further investigation, growing evidence clearly indicates that their ability to interact with βarrestins is relevant for their signaling activities [56]. Therefore, ACKR may be viewed as the prototype of constitutive β-arrestin-biased GPCR [45]. With the exception of ACKR1, whose ability to activate the βarrestin module is not defined, ligand-induced association with β-arrestins has been described for all ACKRs. Each ACKR however shows a unique pattern of recruited β-arrestins, which can be restricted (ACKR2: β-arrestin1; ACKR3: β-arrestin2) or promiscuous (ACKR4 and ACKR5) [33]. With the remarkable exception of ACKR4, β-arrestin coupling has long been considered mandatory for trafficking and scavenger function of all ACKRs [57–59]. Similarly to other chemoattractant receptors [60], a role for β-arrestins in chemokine degradation by modulation of the intracellular receptor transport has been demonstrated for ACKR2 [57] and ACKR3 [58,61], though recent evidence implies β-arrestin recruitment to be overlapped but functionally unrelated to the scavenging activity of ACKR3 [62].

ACKRs ligands. In fact, differently from transporter and presenter, scavenger ACKRs exhibit constitutive trafficking as a mechanism to immediately cope with changes in chemokine needs within the tissue. Interestingly, constitutive trafficking correlates with ACKRs cellular localization, as scavenger ACKRs are mainly located in the cytoplasm shuttling within recycling endosomes [65,66], whereas transporter and presenter are preferentially distributed on the plasma membrane [22,41]. Ligand stimulation promotes mechanisms to increase ACKRs activity by improving receptor internalization for transporters [67] and accelerating recycling routes of scavengers [59,65,68]. Under specific conditions ACKRs are also co-expressed on leukocytes together with their conventional counterparts, and in these cases they fine tune the biological response to chemokines not only sequestering the ligand but also interfering with the activation of conventional chemokine receptors [29,69–72]. The ability to interfere with conventional chemokine receptors signaling represents an additional mechanism used by all ACKRs to exert their regulatory activity. Interestingly, this effect goes beyond direct competition with cognate ligands or ability to form oligomers with conventional counterparts, as it has been clearly demonstrated that some ACKRs (ACKR2 and ACKR4) impair signaling activity of non-cognate conventional chemokine receptors mainly by sequestering β-arrestins and affecting the efficiency of its coupling to conventional receptors [72,73]. Finally, increasing evidences indicate that ACKRs functions goes beyond mere chemokine regulatory activity. ACKR3 and ACKR5 recognize the no-chemokine ligands, and ACKR3 also acts as a mitogenic signal in cancer cells through a mechanism involving constitutive βarrestin-independent Src-dependent transactivation of EGFR [74,75].

2.5. Mechanism of action ACKRs exert their immune-modulatory functions by acting as “checkpoints” of chemokine availability, shaping the chemokine gradient in a spatiotemporal and context-dependent manner, implying a key role for this receptor subfamily in the control of tissue reactions to injury and alarmins activity (Fig. 2). Depending on the mechanism used to fulfill this function, ACKRs can be divided into three main functional categories: scavengers, transporters, and presenters [33,63]. Chemokine scavenging represents the leading mechanism as it is shared by most of ACKRs (ACKR2, ACKR3, ACKR4), while chemokine transport and presentation are restricted to ACKR1 and ACKR5, respectively. Noteworthy, when expressed on erythrocytes ACKR1 also can act as a chemokine sink/reservoir. A scavenger activity has been originally hypothesized for ACKR5, but a recent publication clearly demonstrated that this receptor is devoid of ligand scavenging properties and exclusively functions as an anchoring protein on the surface of endothelial cells [64]. ACKRs ability to fine tune the chemokine gradient relies on their unique trafficking properties, which dictate the intracellular fate of

3. Biological functions of ACKR In the last decade accumulating evidence has clearly established a key role of ACKRs as regulators of immune and inflammatory responses, exerted by their ability to scavenge, transport, or store chemokines [8,9,76]. As mentioned, they also regulate the activity of conventional chemokine receptors with which they share the ligands by forming 3

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control excessive Th17 responses that can lead to immunopathology [98].

heterodimers or modulating their expression levels and signaling activity. Subsequently, the use of gene-targeted mice and the study of human ACKR genetic variants has also revealed their relevance in tumor biology. Initially thought to be directly related to their role as negative regulators of inflammation, new and unexpected ACKR functions have subsequently emerged.

3.2. Role of ACKRs in hematopoiesis Hematopoiesis, which takes place in the bone marrow and in secondary lymphoid organs throughout the adult life, is the process by which mature blood cells differentiate from a common hematopoietic stem cells (HSC) [99]. In hematopoietic organs, HSC reside inside areas called “niches” that are formed by mesenchymal cells and endothelial vessels [100]. It is known from a long time that these stromal cells produce cytokines that act on HSC and thus have a major impact on hematopoiesis [101]. Chemokines and their receptors are also important players in this process [102,103]. In particular, CXCL12 is fundamental for HSC homeostasis [104], and several inflammatory chemokines have myelosuppressive activity and control mobilization of mature and immature leukocytes [105]. Considering their role as regulators of chemokine bioavailability, it is not surprisingly that also ACKRs have a role in hematopoiesis. In particular, several data indicate that ACKR1 and ACKR2 are central controllers of myeloid differentiation [106,107]. Healthy individuals of African ancestry bearing a specific ACKR1 variant are neutropenic [83]. In this context, Duchene and colleagues have recently found that ACKR1 is expressed by bone marrow nucleated erythroid cells. Using a conditional mouse model, they demonstrated that the expression of ACKR1 in these cells is required for their direct interaction with HSC and for neutrophil differentiation [108]. The role of ACKR1 in myeloid differentiation has been recently confirmed in a GWAS study [109]. Similarly to ACKR1, a role for ACKR2 in hematopoiesis has been suggested by the observation that a polymorphism in the ACKR2 gene is linked to altered number of circulating monocytes [110], and direct evidence was then provided by studies performed with ACKR2−/− mice that have detected increased number of circulating inflammatory monocytes [91] and increased myeloid differentiation of HSC [111]. Data on the role of other ACKRs on hematopoiesis are scanty. ACKR4 was found to be a regulator of B cell differentiation, as it limits migration of B cells in the splenic interfollicular zones and, as a consequence, it reduces the numbers of activated B cells [112]. Being a high affinity receptor for CXCL12 [113], ACKR3 also likely has a role in hematopoiesis, though at present no data are available.

3.1. Role of ACKRs in the regulation of immune responses In vivo models of acute and chronic inflammation using full Ackr1−/ mice have originally indicated a prominent proinflammatory role exerted by ACKR1. Indeed Ackr1−/− mice display reduced neutrophil recruitment in acute lung and kidney injury models, which results in tissue protection [77–80]. Ackr1−/− mice are also partially protected from atheroma development [81], but when subjected to high fat diet show increased adipose tissue inflammation and weight gain, despite having lower levels of circulating CCL2 [82]. These divergences could be reconciled by the fact that ACKR1 prominent function depends upon its expression profile. Indeed, when expressed by erythrocytes ACKR1 functions as a “sink” for inflammatory chemokines, thus limiting excessive leukocyte extravasation. Consistent with this, individuals of African origin who lack ACKR1 expression on erythrocytes (referred to as “Duffy-null”) have higher concentrations of circulating chemokines [73,83]. On the contrary, when expressed on endothelial cells ACKR1 supports chemokine internalization and transcytosis and presents inflammatory chemokines on the luminal surface of vessels [22], thus promoting inflammation. Differently from ACKR1, ACKR2 has been reproducibly shown to limit inflammation and promote its resolution. Indeed, the impaired clearance of inflammatory chemokines observed in Ackr2−/− mice results in increased inflammation in response to infectious agents [84], ischaemic damage [85], and in several inflammatory models related to various tissues, including skin, gut, lung, kidney, joints, and placenta [86–89]. ACKR2 also limits the induction of adaptive immune responses, as Ackr2−/− mice are resistant to the induction of experimental autoimmune encephalomyelitis [90], and are protected from GVHD [91]. The mechanism of the protective effect of ACKR2 in adaptive immunity is still unclear. ACKR2 deficiency does not suppress autoreactive T-cell priming but enhances T-cell polarization toward Th17 cells [92]. Ackr2−/− mice are also protected from renal inflammation and renal fibrosis in a model of diabetic nephropathy [87] and from bleomycin-induced lung fibrosis [93]. In this latter model the mechanism of protection was correlated with increased IFNγ-producing γδT cell influx and reduced Th17 response. Opposite to ACKR2, evidence indicates a proinflammatory role for ACKR3. Endothelial cells increase ACKR3 expression during inflammatory reactions, and lymphocytes purified from inflammatory bowel disease patients show enhanced ACKR3 expression [94]. ACKR3 is also expressed by macrophages in the atherosclerotic plaque, where it was associated with a pro-inflammatory phenotype that included production of inflammatory chemokines and phagocytic activity [95]. Similarly, ACKR3 expressed by rheumatoid arthritis synovium promotes the inflammatory process by increasing angiogenesis [96] and is also expressed by brain microvascular endothelial cells during experimental inflammatory conditions, such as permanent middle cerebral artery occlusion and experimental autoimmune encephalomyelitis, where it favors leukocyte extravasation by enhancing leukocyte adhesion to the endothelial surface [97]. Thus, ACKR3 promotes immune responses by enhancing leukocyte extravasation and promoting leukocyte pro-inflammatory activities. Though data on the role of ACKR4 in immune responses are scanty, this ACKR appears to be an important regulator of the adaptive immune response. Indeed, ACKR4 expression in lymph nodes is necessary for creating a gradient of the CCR7 ligands, CCL19 and CCL21, in the subcapsular sinus [14]. In addition, using ACKR4−/− mice, it was demonstrated that homeostatic chemokine clearance is necessary to −

3.3. Role of ACKRs in tumor biology Chemokines are key mediators of chronic inflammatory processes, and their expression is often regulated by oncogenic pathways and transcription factors deregulated in the pathogenesis of cancer, being therefore important players in both pathways linking inflammation to cancer [114]. Chemokines control several aspects of tumor biology, including immune infiltrate at the primary tumor site, the angiogenesis process, cancer cell proliferation, and migration to metastatic sites [114]. Both preclinical observations obtained in ACKR gene‐targeted mice and clinical data provide evidence that the regulation exerted by ACKRs on the chemokine system has an important role in cancer biology [115]. The role of ACKR1 has been evaluated in different tumor models. ACKR1 overexpression in breast and lung cancer cell lines inhibited tumor angiogenesis and metastasis [116,117], and transgenic mice overexpressing ACKR1 on endothelial cells displayed reduced growth and angiogenesis when injected with the human melanoma cell line Mela [118]. ACKR1 overexpression in pancreatic ductal adenocarcinoma cells also inhibited their proliferation by suppressing STAT3 activation through the inhibition of CXCR2 signaling [119]. In addition, other studies indicated that ACKR1 expressed by endothelial cells can inhibit metastasis, with a mechanism unrelated to its chemokine control activity. Indeed, ACKR1 interaction with the tetraspanin CD82/KAI expressed by tumor cells resulted in increased p21 levels, inducing their 4

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and colleagues have reported that ACKR3 inhibits breast tumor metastasis by decreasing CXCR4‐mediated effects, such as production of metalloproteinase‐12 and matrix degradation [144], and ACKR3 expression was also correlated with a reduced metastatic phenotype in rhabdomyosarcomas [145]. Also the role of ACKR3 in tumor angiogenesis is at present controversial. ACKR3 is expressed by endothelial progenitors and tumor endothelial cells and it has been reported to have a proangiogenic role by inducing endothelial progenitor transendothelial migration and survival [146,147]. However, an opposite role for endothelial ACKR3 was found by the use of conditional knockout mice with selective depletion of the receptor in vascular endothelial cells, as by decreasing CXCL12 plasma levels ACKR3 protected these animals from lung metastasis in breast cancer after orthotopic injection of the AT‐3 cell line [148]. ACKR3 expression by endothelial cells was also correlated with a better prognosis in patients with glioblastoma [149], and in a murine model of glioblastoma ACKR3 monoclonal antibodies in combination with the chemotherapy agent temozolomide induced the killing of tumor and endothelial cells by NK and macrophages and resulted in extended survival [150]. These results indicate that ACKR3 has multiple roles in tumor biology, not restricted to its ability to regulate CXCL12 bioavailability and CXCR4 signaling but also involving direct activation of intracellular G protein–independent pathways that promote cell growth and survival. Despite its expression by tumor cells being correlated in most of the cases with an increase in tumor growth, contrasting results have been reported on its role for metastatic spread, as it can protect from metastatic dissemination but also promote angiogenesis. Few results have been published on the role of ACKR4 in cancer biology. in vitro, ACKR4 overexpression inhibited proliferation of some breast and hepatocellular carcinoma cell lines [151,152]. In vivo, beside inhibition of tumor growth, there is also evidence for reduced metastasis. ACKR4 overexpression in a colon cancer model reduced tumor cell migration and matrigel invasion [153]. This result is in line with the protective role of ACKR4 in tumor growth and dissemination in human breast, hepatocellular, and colon cancer samples, in which ACKR4 down‐regulation is correlated with worse outcome [151–153]. Opposite results however have been found using the breast cancer cell line 4T1.2 overexpressing ACKR4, which displayed increase levels of TGF‐β1, enhanced EMT, and increased lung metastasis [154].

senescence and inhibiting lung metastasis [120,121]. Consistent with its protective role, Ackr1−/− mice showed enhanced prostate cancer growth correlated with increased levels of angiogenic CXC chemokines, such as CXCL8 and CXCL2 [122]. Despite this preclinical result however, no correlation between the “Duffy-null” phenotype and the higher prostate cancer incidence reported in African American people was found [123]. A protective role of ACKR1 in cancer is also suggested by data referring to human tumors. In breast, thyroid, colorectal, laryngeal squamous cell and pancreatic tumors, ACKR1 expression was positively correlated with a better outcome, even if the cell types expressing ACKR1 in these samples were not characterized [116,119,124–128]. In summary, evidence indicates ACKR1 as a negative regulator of tumor growth, with inhibitory effects on tumor angiogenesis and metastasis largely mediated by reducing angiogenetic chemokine levels. As mentioned, ACKR2 acts as a CC inflammatory chemokine scavenger, inhibiting leukocytes recruitment and limiting inflammation. Consistently with this, ACKR2 was found protective in different inflammation-induced tumor models, such as the TPA/DMBA skin and the AOM/DSS colon cancer models [129]. Conversely, despite its expression resulted in decreased inflammation, no difference was found on tumor growth in the diethylnitrosamine-induced liver cancer and oral squam cancer models [130,131]. ACKR2 expression was found downregulated in human cancer samples, such as colon adenocarcinoma and Kaposi sarcoma [23,132]. In this latter tumor, ACKR2 down‐regulation was directly dependent by the oncogenic pathway KRas/B-Raf/MEK/MAPK and was particularly evident in more‐aggressive forms [23]. Similarly, expression of ACKR2, ACKR1, and ACKR4 was correlated with a better outcome also in cervical squamous cell cancer and gastric cancer [25,133]. Conversely, in the ApcMin/+ model of intestinal tumor, where inflammatory chemokines are needed to establish a mast cell-dependent process of CD8+ T-cell recruitment which mediate immune surveillance, ACKR2 plays a protumoral role. Similarly, in breast cancer ACKR2 expression was found to be inversely correlated with lymph node metastasis and clinical stage and positively correlated to disease‐free survival rate [124], and similar findings have been reported for human lung cancer [134]. Collectively, these results indicate that the chemokine scavenger activity of ACKR2 results in protection from cancer growth when recruited leukocytes sustain and enhance tumor growth, while having an opposite effect in experimental settings where a protective immune response is required. In line with this latter scenario, we recently reported that Ackr2−/− mice are protected by metastasis in breast cancer and melanoma models as the consequence of the release from the bone marrow of neutrophils with antimetastatic activity in ACKR2−/− mice [111]. ACKR3 was found up‐regulated on several tumors and on tumorassociated endothelial cells [135], with a mechanism involving hypoxia, DNA methylation of the tumor suppressor gene hypermethylated in cancer 1, and expression of microRNA‐430 and microRNA‐101 [136]. Different from the other ACKRs, ACKR3 clearly promotes tumorigenesis by increasing tumor cell proliferation and inhibiting apoptosis. In particular, in lung cancer TGF‐β1 increased ACKR3 expression and this correlated with decreased survival rate [137], while in breast and prostate cancers ACKR3 was reported to form heterodimers with EGFR and promote tumor cell proliferation in a ligand‐independent way [74,138,139]. ACKR3 expression has also been correlated with poor prognosis in renal cell carcinoma, where it promoted tumor growth by activating the mTOR pathway [140]. While the role of ACKR3 in promoting cancer growth is well assessed, the role of ACKR3 in the metastasis process is contrasting. This receptor was found to promote metastasis in a breast cancer model [141] as well as in hepatocellular carcinoma through up‐regulation of osteopontin [142], was required for bone marrow and brain invasion and for local tumor growth in a disseminated in vivo lymphoma model [30], and was also reported to regulate CXCR4‐mediated transendothelial migration of tumor cells [143]. On the contrary, Hernandez

4. Conclusions After infection or tissue damage, alarmins are release in the extracellular milieu and prime host defense responses. A downstream effector is represented by chemokines, which are recognized as the main drivers of leukocyte recruitment during inflammatory reactions. Mechanisms controlling chemokines biological activities are therefore key to regulate tissue reactions induced by alarmins. By different mechanisms, including transport, presentation and scavenging, atypical chemokine receptors shape chemokine gradients in tissues and are emerging as a new family of chemokine gatekeepers in inflammation and cancer. Funding sources This work was supported by the The Italian Association for Cancer Research (AIRC-IG 2016 #19014 to ML and #20269 to RB) and the Italian Ministry of Health (Ricerca Finalizzata GR-2013-02356521 to EMB and GR-2013-02356522 to BS). References [1] I.F. Charo, R.M. Ransohoff, The many roles of chemokines and chemokine receptors in inflammation, N. Engl. J. Med. 354 (6) (2006) 610–621. [2] F. Bachelerie, A. Ben-Baruch, A.M. Burkhardt, C. Combadiere, J.M. Farber, G.J. Graham, R. Horuk, A.H. Sparre-Ulrich, M. Locati, A.D. Luster, A. Mantovani,

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