Seminars in Immunology xxx (xxxx) xxx–xxx

Contents lists available at ScienceDirect

Seminars in Immunology
journal homepage: www.elsevier.com/locate/ysmim

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,
a
Humanitas Clinical and Research Center, Via Manzoni 113, I-20089 Rozzano, Italy
b
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

A R T I C LE I N FO A B S T R A C T

Keywords: As main drivers of leukocyte recruitment during inflammatory reactions, chemokines act as mediatrs of alarmins
Chemokines in priming host defense responses after tissue exposure to toxic or infectious agents, immunomediated damage,
Scavenger receptors and in inflammation-driven tumors. Chemokines can therefore be considered alarm signals generated by tissues
Atypical chemokine receptors in a broad number of conditions, and mechanisms controlling chemokines biological activities are therefore key
Cancer related inflammation
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 op-
erates in tissues as chemokine gatekeepers in order to establish and shape their gradients and coordinate leu-
kocyte recruitment.

1. Introduction receptors. The chemokine receptors family includes 10 receptors re-

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 pro-
cess. 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 li-
gands 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 amino-
terminus of the protein. The relative positioning of these cysteine re-
sidues 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 re-
sidues separating the cysteine tandem, respectively). This structure-
based chemokine classification is reflected in the classification of their
cognizing CC chemokines (CCR1 to 10) and 6 recognizing CXC che-
mokines (CXCR1 to 6), plus 2 receptors (XCR1 and CX3CR1) re-
cognizing the only known C and CX3C chemokine known, respectively
[2]. These 18 receptors represent a distinct subfamily of the G protein-
coupled 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 activ-
ities 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 pro-
cessing at the amino- and carboxyl-termini by proteases and mod-
ifications 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].

⁎
Corresponding author at: Humanitas Clinical and Research Center, Via Manzoni 113, 20089 Rozzano, Italy.
E-mail addresses: elena.borroni@unimi.it (E.M. Borroni), benedetta.savino@humanitasresearch.it (B. Savino),
raffaella.bonecchi@humanitasresearch.it (R. Bonecchi), massimo.locati@humanitasresearch.it (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
E.M. Borroni et al.
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
As mentioned, conventional chemokine receptors represent a well-
characterized GPCR subfamily able to directly induce leukocyte mi-
gration. 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).
2.1. Expression pattern
Though ACKRs have been reported in some leukocyte subsets, in-
cluding hematopoietic progenitors, B and T lymphocytes and alveolar
macrophages, as well as erythrocytes, differently from their conven-
tional counterparts ACKRs are usually poorly expressed within the he-
matopoietic 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]) en-
dothelial cells. In some cases they may display distinct functions de-
pending upon their expression profile, as exemplified by ACKR1 that
acts as a chemokine sink on erythrocytes and as a chemokine trans-
porter 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 micro-
environment 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 re-
ported 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].
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2.2. Ligands
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 Mi-
gration-Inhibitory Factor [38], as well as adrenomedullin and the in-
termediate opioid peptide BAM22 [39,40], and ACKR5 binds the che-
moattractant chemerin [41]. This evidence indicates that ACKRs exert
control on leukocyte chemoattraction beyond the chemokine system
borders.
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 re-
lationship 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 sul-
fated 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 N-
terminus of ACKR2 is essential for ligand internalization. Of note, a
sulfated peptide derived from this region is capable of binding in-
flammatory 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 con-
served structural determinants in TM domains involved in “micro-
E.M. Borroni et al.
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 sig-
nificant 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 re-
ceptor/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 C-
terminal 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
GPCR are currently thought to signal through G protein and β-ar-
restin 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 re-
ceptors [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 cou-
pling and signaling properties of ACKRs deserve further investigation,
growing evidence clearly indicates that their ability to interact with β-
arrestins 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 β-
arrestin module is not defined, ligand-induced association with β-ar-
restins 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].
2.5. Mechanism of action
ACKRs exert their immune-modulatory functions by acting as
“checkpoints” of chemokine availability, shaping the chemokine gra-
dient 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]. Chemo-
kine 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 ex-
clusively 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
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Seminars in Immunology xxx (xxxx) xxx–xxx
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 acti-
vation 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 re-
ceptors expressed on endothelial cells and other non-leukocyte cells also tune
chemokine concentrations by transporting or degrading them.
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 leuko-
cytes together with their conventional counterparts, and in these cases
they fine tune the biological response to chemokines not only seques-
tering the ligand but also interfering with the activation of conventional
chemokine receptors [29,69–72]. The ability to interfere with conven-
tional chemokine receptors signaling represents an additional me-
chanism used by all ACKRs to exert their regulatory activity. Interest-
ingly, 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 re-
cognize the no-chemokine ligands, and ACKR3 also acts as a mitogenic
signal in cancer cells through a mechanism involving constitutive β-
arrestin-independent Src-dependent transactivation of EGFR [74,75].
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
E.M. Borroni et al.
heterodimers or modulating their expression levels and signaling ac-
tivity. 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 func-
tions have subsequently emerged.
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 ex-
cessive 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 in-
flammatory 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 re-
sponses, as Ackr2−/− mice are resistant to the induction of experi-
mental 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 in-
flammation 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 in-
flammatory 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 pro-
duction of inflammatory chemokines and phagocytic activity [95]. Si-
milarly, 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-in-
flammatory 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 de-
monstrated that homeostatic chemokine clearance is necessary to
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Seminars in Immunology xxx (xxxx) xxx–xxx
control excessive Th17 responses that can lead to immunopathology
[98].
3.2. Role of ACKRs in hematopoiesis
Hematopoiesis, which takes place in the bone marrow and in sec-
ondary 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 im-
portant 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 con-
sequence, 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.
3.3. 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 adenocarci-
noma cells also inhibited their proliferation by suppressing STAT3 ac-
tivation 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
E.M. Borroni et al.
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 how-
ever, 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 re-
ferring 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 sca-
venger, inhibiting leukocytes recruitment and limiting inflammation.
Consistently with this, ACKR2 was found protective in different in-
flammation-induced tumor models, such as the TPA/DMBA skin and
the AOM/DSS colon cancer models [129]. Conversely, despite its ex-
pression 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 adenocarci-
noma and Kaposi sarcoma [23,132]. In this latter tumor, ACKR2
down‐regulation was directly dependent by the oncogenic pathway K-
Ras/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 in-
testinal tumor, where inflammatory chemokines are needed to establish
a mast cell-dependent process of CD8+ T-cell recruitment which med-
iate 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 re-
ported 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 tumor-
associated endothelial cells [135], with a mechanism involving hy-
poxia, 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 tu-
morigenesis by increasing tumor cell proliferation and inhibiting
apoptosis. In particular, in lung cancer TGF‐β1 increased ACKR3 ex-
pression 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‐indepen-
dent 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 as-
sessed, 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 transen-
dothelial migration of tumor cells [143]. On the contrary, Hernandez
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Seminars in Immunology xxx (xxxx) xxx–xxx
and colleagues have reported that ACKR3 inhibits breast tumor me-
tastasis by decreasing CXCR4‐mediated effects, such as production of
metalloproteinase‐12 and matrix degradation [144], and ACKR3 ex-
pression was also correlated with a reduced metastatic phenotype in
rhabdomyosarcomas [145]. Also the role of ACKR3 in tumor angio-
genesis 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 transen-
dothelial 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 an-
tibodies in combination with the chemotherapy agent temozolomide
induced the killing of tumor and endothelial cells by NK and macro-
phages 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 sur-
vival. 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 metas-
tasis. 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].
4. Conclusions
After infection or tissue damage, alarmins are release in the extra-
cellular milieu and prime host defense responses. A downstream ef-
fector 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 me-
chanisms, 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).
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