Download Role of Chemokines and Chemokine Receptors

Published OnlineFirst December 7, 2012; DOI: 10.1158/0008-5472.CAN-12-2027
Cancer
Research
Review
Role of Chemokines and Chemokine Receptors in Shaping
the Effector Phase of the Antitumor Immune Response
re2, and
Katarzyna Franciszkiewicz1, Alexandre Boissonnas2, Marie Boutet1, Christophe Combadie
Fathia Mami-Chouaib1
Abstract
Immune system–mediated eradication of neoplastic cells requires induction of a strong long-lasting
antitumor T-cell response. However, generation of tumor-specific effector T cells does not necessarily result
in tumor clearance. CTL must first be able to migrate to the tumor site, infiltrate the tumor tissue, and
interact with the target to finally trigger effector functions indispensable for tumor destruction. Chemokines
are involved in circulation, homing, retention, and activation of immunocompetent cells. Although some of
them are known to contribute to tumor growth and metastasis, others are responsible for changes in the
tumor microenvironment that lead to extensive infiltration of lymphocytes, resulting in tumor eradication.
Given their chemoattractive and activating properties, a role for chemokines in the development of the
effector phase of the antitumor immune response has been suggested. Here, we emphasize the role of the
chemokine–chemokine receptor network at multiple levels of the T-cell–mediated antitumor immune
response. The identification of chemokine-dependent molecular mechanisms implicated in tumor-specific
CTL trafficking, retention, and regulation of their in situ effector functions may offer new perspectives for
development of innovative immunotherapeutic approaches to cancer treatment. Cancer Res; 72(24); 6325–32.
2012 AACR.
Introduction
The identification of tumor-associated antigens (TAA) and
the isolation of tumor-specific cytotoxic T cells have led to
great efforts in developing immunotherapeutic approaches to
overcoming tumor invasion. Immunotherapy represents a
promising approach to cancer treatment, with less severe side
effects than conventional strategies. Major strategies have
focused on the induction of T-cell–mediated antitumor
responses. However, the generation of antigen-specific
tumor-reactive T cells has rarely been translated into therapeutic success. One of the reasons for the failure of the immune
system to eradicate cancer cells is a defect in T-cell migration
to the tumor site (1). To destroy established tumors, CTL must
traffic to and infiltrate the tumor tissue before specific activation and triggering of target cell death. The dissection of
cellular and molecular processes that enhance T-cell recruitment and ultimately lead to tumor elimination is therefore a
et de la Recherche
Authors' Affiliations: 1Institut National de la Sante
Medicale (INSERM) U753, Team 1: Tumor Antigens and T-cell Reactivity,
Integrated Research Cancer Institute in Villejuif (IRCIV), Institut de
rologie Gustave Roussy (IGR), Villejuif; and 2INSERM UMR-S 945
Cance
Pierre et Marie Curie (UPMC University Paris 06), Laboratory
and Universite
^ pital, Paris, France
of Immunity and Infection, Boulevard de l'Ho
Corresponding Author: Fathia Mami-Chouaib, Institut National de la
et de la Recherche Medicale (INSERM) U753, IGR, 39 rue
Sante
Camille-Desmoulins, F-94805 Villejuif, France. Phone: 33-1-42-11-4965; Fax: 33-1-42-11-52-88; E-mail: [email protected]
doi: 10.1158/0008-5472.CAN-12-2027
2012 American Association for Cancer Research.
critical step in optimization of current cancer immunotherapy
protocols.
Chemokines coordinate circulation, homing, and retention
of immune cells. Originally characterized for their ability to
induce leukocyte chemoattraction, they are now recognized to
orchestrate a wide array of leukocyte functions during inflammation and immunity (2). Indeed, in addition to their chemotactic properties, chemokines can directly regulate T-cell
development, priming, and effector functions (3). In the context of cancer immunosurveillance, chemokines orchestrate
the spatiotemporal distribution of immunocompetent cells
crucial for induction of antitumor immune response and
optimal effector function (4, 5). Chemokines constitute a large
family of small, mostly secreted proteins comprising more than
50 members, which interact with 20 chemokine receptors.
Chemokine receptors are G-protein–coupled 7-transmembrane–domain receptors responsible not only for triggering
intracellular signals resulting in cell polarization, migration,
and adhesion, but also for contributing to gene expression, cell
proliferation, and survival (2). Most chemokines bind to more
than 1 receptor. On the other hand, chemokine receptors
display overlapping ligand specificities with variable affinity
and functional activities (3).
There is now overwhelming evidence that the chemokine–
chemokine receptor system is directly or indirectly involved in
tumor development (6). On the basis of their role in cell
migration, chemokines contribute to tumor dissemination
and metastasis. Moreover, chemokine-triggered signaling
pathways can facilitate tumor cell proliferation and contribute
to neovascularization. Tumor-derived chemokines are also
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Franciszkiewicz et al.
responsible for shaping the tumor microenvironment into an
immunosuppressive site, determining the qualitative and
quantitative composition of tumor-infiltrating immune cells
and affecting their maturation and activation status (7). In
consequence, tumors seem to use chemokines to evade immunosurveillance and actively progress. Nevertheless, expression
of some chemokines within the tumor bed has been associated
with an effective antitumor immune response, an angiostatic
effect, a low recurrence rate and increased patient survival.
Indeed, some chemokines are responsible for changes in
chemoattractive properties of the tumor microenvironment
that allow extensive infiltration of leukocytes (7). Thus, chemokines and chemokine receptors represent valuable targets
for optimizing antitumor immune responses. In this context,
the major concern of tumor immunologists is to better understand chemokine-mediated pathways involved in T-cell
recruitment at the tumor site and in regulating their intratumoral effector functions. In this review, we present findings
implicating chemokines in regulation of the CTL-mediated
effector phase of the antitumor immune response and we
provide insights into their therapeutic applications.
Role of Chemokines in Priming the T-Cell–
Mediated Immune Response
Development of an effective antitumor immune response
relies on the coordinated interactions of immunocompetent
cells, the spatiotemporal distribution of which is in part
orchestrated by chemokines (Fig. 1). Acting through their
cognate receptors, chemokines regulate trafficking between
the tumor site and lymph nodes. To become competent killer
cells, CTL require efficient priming by professional antigenpresenting cells (APC) and cognate licensing of dendritic cells
by CD4þ T cells (8). For this purpose, na€ve CD8þ T cells
continuously traffic through secondary lymphoid organs in
which they systematically scan the surface of dendritic cells
searching for TAA. Na€ve T cells express CCR7, which recognizes constitutively expressed CCL19 and CCL21. CCL21, produced by lymph nodes, Peyer's patch–associated high endothelial venules, and afferent lymphatic vessels, triggers a multistep process for recruitment of na€ve lymphocytes (9). Similarly, CCL21-CCR7 signaling is involved in trafficking of
antigen-presenting dendritic cells. Indeed, their maturation
into potent APC implies downregulation of tissue-specific
chemokine receptors, such as CCR1, CCR5, and CCR6, and
upregulation of CCR7, which guides dendritic cells from sites of
antigen exposure to the local lymph nodes via draining afferent
lymphatic vessels (10). The pivotal role of CCR7 in these
processes was shown in CCR7-deficient mice, which displayed
reduced numbers of na€ve T cells in secondary lymphoid
organs (11). Once in the lymph nodes, T cells display high
basal motility, enabling them to scan up to several thousand
APC per hour. These steady-state movements are dependent
on Gai-coupled chemokine receptor signaling triggered by
CCL19 and CCL21 present in the lymph node T-cell zone (12).
The major biologic relevance of na€ve T-cell motility within
lymph nodes is to ensure recognition of a few antigen-bearing
dendritic cells by rare specific T cells. However, random
migration of T cells does not seem to be efficient enough to
6326
Cancer Res; 72(24) December 15, 2012
provide CD4 T-cell help for CD8 T-cell priming, where 2
lymphocyte types have to encounter the same APC (13). It has
been shown that CCL19 secreted by mature dendritic cells
increases na€ve CD4 T-cell scanning behavior and their
response to rare cognate antigens (14). Moreover, engagement
of na€ve CD4 T cells with APC triggers secretion of CCL3 and
CCL4, which favor CCR5-dependent guidance of na€ve CD8 T
cells toward dendritic cells (DC)-CD4 T-cell conjugates (15).
Interestingly, CCR5-dependent recruitment of CD8 T cells to
dendritic cells engaging TAA-specific T cells increases the
efficiency of alternative TAA-specific na€ve CD8 T-cell priming
(16).
Following the antigen encounter and T-cell expansion, a
modification in the general chemokine receptor expression
profile is required to enable appropriate redistribution of
activated T cells. This modification consists of downregulation
of receptors that mediate entry and the encounter with APC in
the lymph node, and of upregulation of other receptors to first
egress from the lymph node and then sensitize T cells to
infiltrate the tumor site. Pertussis toxin has been shown to
affect lymphocyte egress from the lymph node, suggesting an
implication of chemokine receptors. Indeed, one of the initial
events in effector T-cell differentiation is downregulation of
CCR7 and upregulation of receptors specific to chemokines
expressed in target tissues, such as CCR1, CCR2, CCR3, CCR5,
and CXCR3 (17). Acquisition of an appropriate migration
program is thus crucial for targeting the right cell to the right
place.
Regulation of T-Cell Recruitment at the Tumor
Site by Chemokines
To exert their functions, recently primed T cells leave the
lymph node and migrate to the tumor site, in which they
physically engage cognate T-cell receptor (TCR) ligand-expressing targets. Chemokines play a major role in the recruitment
of effector T cells within the tumor microenvironment. Antitumor CTL respond to numerous inflammatory chemokines,
mainly CCL3 (18), CCL5 (19), CCL20 (20), and CXCL10 (21),
which can be produced at the tumor site (22). Therefore, the
intratumoral production of chemokines, which determine
optimal T-cell recruitment, is one of the key factors in an
efficient antitumor immune response. In this context, CCL5
was one of the first chemokines implicated in regulating
antitumor immunity (19). A role for CCR5 in T-cell recruitment
to the tumor site has been documented and local production of
CCL5 or CCL3 induces selective recruitment of CD8 T cells and
CTL-dependent tumor suppression in mouse models (23).
CCR5 ligands are detected in many human tumors, including
non–small-cell lung carcinoma (NSCLC), and can induce T-cell
infiltration. However, the role of CCL5 in the antitumor
immune response remains controversial. In NSCLC, the production of CCL5 has been associated with an active lymphocyte-mediated response and represents a positive predictive
factor for patient survival (24). In contrast, high levels of CCL5
have been reported to correlate with poor prognosis in breast
and cervical carcinomas (25). Although the cellular infiltrates
were not investigated in these studies, it is conceivable that
disease progression was related to tumor escape mechanisms
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Published OnlineFirst December 7, 2012; DOI: 10.1158/0008-5472.CAN-12-2027
Chemokines and the Antitumor Immune Response
Lymph node
MHC-II-TCR
Migration to
LN
Maturation
CD4ⴙ
T cell
CD4
CCR7
CD40–CD40L
CCL19, 21
IL-2,
IFNγ…
DC
Ag
presentation
MHC-I-TCR
IDC
CD8
CD8ⴙ
T cell
CD80/86-CD28
CCR1, 5, 6, 9
CXCR4
Ag
uptake
Innate
immunity
Adaptive
immunity
CCR2, 5
CXCR3
CCR2, 5, 9
CXC3R1
M␾
NK
CCR1, 2, 4, 5, 7, 8
CXCR1, 2, 3, 4
(HSP, Calreticulin…)
XCR1
NKT
Lysis
CCL2, 3, 5, 16
Dying tumor
cells
CXCL8, 9, 10, 12, 21
CCR5, 6
CXCR3, 4, 6
Danger signals
CCL3
CCL4
CCL3, 4, 5
Migration to
the tumor
CXCL9, 10, 11
CXCL10, 12, 16
PRR
CD4ⴙ Th1 cell
CCR5
CXCR3
XCL1
IFNα
DC
precursor
CD8ⴙ CTL
Specific lysis
PAMP
CCR3, 4, 8
Treg
CD4ⴙ Th2 cell
CCR2, 4, 5, 6, 8
CCR2, 4, 5, 6, 8
MDSC
Tumor site
Figure 1. Chemokine network in the antitumor immune response. Malignant cells express pathogen-associated molecular patterns (PAMP) that
can be recognized by pattern recognition receptors (PRR) on dendritic cells (DC) and macrophages (M), triggering release of chemokines.
This results in recruitment and activation of M, NK, and NKT cells, which are able to lyse tumor cells. DC phagocytose apoptotic tumor cells and
HSP-complexed tumor-derived peptides. Upon maturation, DC change their homing proprieties by downregulating tissue-specific chemokine
receptors and upregulating CCR7 that guides them to CCL19/CCL21-rich lymph nodes (LN), where they present processed tumor
þ
þ
peptides to CD4 and CD8 T cells. Activated T cells upregulate expression of chemokine receptors including CCR5 and CXCR3, and in
response to intratumoral chemokines, circulating CTL infiltrate the tumor to destroy malignant cells. Tumor-derived chemokines are also
responsible for recruitment of Treg cells and MDSC, which participate in establishment of a protumoral microenvironment. Ag, antigen; IDC,
immature DC.
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Franciszkiewicz et al.
6328
through concurrent recruitment of immunosuppressive cell
populations, such as tumor-associated macrophages and
regulatory T (Treg) cells, or triggering of tumor-infiltrating
lymphocyte (TIL) apoptosis (26). Conversely, other groups
provided evidence for CCL3 and CCL5-induced T-cell proliferation and activation (27, 28).
Among other chemokines implicated in tumor infiltration
by immune cells, CX3CL1 and CXCL16 have been associated
with high numbers of CD8þ and CD4þ TIL and with good
prognosis in colorectal cancer (29). CCL20 has been detected in
breast cancer, in which it may be responsible for recruitment of
CCR6þ memory T-cell subsets (30). The main chemokines
attracting effector cells seem to be the CXCR3 ligands CXCL9
and CXCL10. In addition to their angiostatic activity, these
chemokines participate in the antitumor immune response
through recruitment of T and natural killer (NK) cells (23). In
renal cell carcinoma, intratumoral expression of CXCL9 and
CXCL10 coincided with a high degree of CD8 T-cell infiltration
and elicited an inverse correlation with tumor growth and
recurrence after curative surgery (31). High levels of CXCL9
have also been associated with strong infiltration of malignant
melanoma by CD8 T cells and improvement in patient survival
(32). Thus, it seems evident that chemokines contribute to the
establishment of the immune response by orchestrating
the distribution of its key cellular components and delivering
the generated effectors to the tumor site. Whether intratumoral chemokines promote immune surveillance or tumor
escape depends on the composition of cell infiltrates, which
shape the environmental context through an immunoediting
process.
Interestingly, nonspecific tumor T cells can deeply infiltrate
tumor tissues only upon tumor destruction by antigen-specific
CTL (35). This suggests that changes in the tumor microenvironment, such as secretion of chemokines induced by
destruction in tumor architecture, determine deep lymphocyte
infiltration. Therefore, delivery of appropriate chemokines into
the tumor, reminiscent of what takes place during an effective
T-cell response, would induce extensive infiltration of effector
cells, and thereby tumor destruction.
The contribution of chemokine receptors in T-cell retention
at the tumor site is not well documented. We recently reported
that recruitment of CCR5 at the immune synapse formed
between TIL and tumor cells, resulted in inhibition of T-cell
responsiveness to a CCL5 chemotactic gradient. This CCR5
clustering is dependent on the interaction of the aE(CD103)b7
integrin on T cells with its ligand, E-cadherin, on NSCLC cells
(36). An alternative mechanism of CTL retention in epithelial
tumors could implicate CCR6. CCR6þ T cells were found to be
more frequent in CD8 subpopulations isolated from TIL than
from PBL (36). This observation, together with efficient homing
of CCR6 CTL to the tumor site, suggests that CCR6 is not
involved in T-cell recruitment to NSCLC but may play a local
role. Apart from its function in cell trafficking, CCR6 was
reported to be crucial for cell activation and conformational
changes in integrins (37). Furthermore, it has been shown that
the interaction of CCR6 with its unique ligand, CCL20, is a
critical event in the arrest of effector/memory T cells on
endothelial cells (38). It is therefore conceivable that intratumoral induction of CCR6, together with CD103, play a role in Tcell retention at the tumor site.
Intratumoral T-Cell Location, Motility, and
Retention
Costimulatory Role of Chemokines–Chemokine
Receptors in T-Cell Activation
Positioning of CTL within tumor tissues is critical for an
efficient antitumor immune response. After extravasation,
CTL must migrate through the interstitial space of the
tumor to recognize and kill target cells. Thus far, little is
known about the intratumoral migration of infiltrating CTL.
In experimental studies, CD8 T cells were mostly observed at
the tumor periphery, with limited infiltration into the tumor
mass. A similar pattern was identified in human tissue
sections from metastatic melanoma. In NSCLC, T cells
accumulate in stromal regions in which chemokines likely
participate in controlling their motility and their entry into
tumor islets (33).
Before establishing stable contact with target cells, TIL
migrate randomly within the tumor microenvironment, arguing against the early concept of T-cell guidance by a long-range
chemokine gradient. Two-photon microscopy studies provided insight into the dynamics of infiltration and elimination of
solid tumors by immune cells (34, 35). After diapedesis, effector
T cells initially display random migration and start engaging a
transient antigen-independent interaction with target cells.
CTL that encounter antigen-expressing tumor cells, arrest
their migration to establish a stable contact with the target.
This leads to release of cytokines and cytotoxic granules
resulting in tumor cell death. Once cancer cells are cleared,
CTL resume motility to further search for new target cells.
Although there is a considerable evidence implicating chemokines in antigen-experienced T-cell recruitment to the
tumor site, their role in T-cell effector function is begging for
intensified investigation. It has been widely reported that
engagement of chemokine receptors triggers a "go" signal that
competes with TCR-mediated "stop" signals, and thus negatively influences the stability and duration of the immune
synapse (39). Indeed, the gradient of some chemokines, including CXCL10 and CCL19 or CCL21, renders T cells ignorant of
agonist peptide-MHC (pMHC), thus suppressing their activation. However, CCL19 secreted by antigen-activated dendritic
cells induces T-cell polarization and motility, resulting in
improved scanning of APC, thus increasing cognate pMHC
encounters (14).
Chemokines such as CXCL12 were also reported to enhance
adhesion of T cells to dendritic cells by regulating the avidity/
affinity of key integrins, including leukocyte function-associated antigen (LFA)-1 (37). Other chemokines, namely CCR7
ligands bound on dendritic cells surface, may promote T-cell
activation by improving immune synapse formation (40). CCR5
and CXCR4 can be recruited to the immune synapse during Tcell stimulation by APC, leading to a reduction in T-cell
sensitivity to other chemokine sources and enhanced T-cell
responses (27). It has also been proposed that APC-derived
chemokines can act as costimulatory molecules for engaged T
Cancer Res; 72(24) December 15, 2012
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Prostate cancer (M), breast
cancer (M), melanoma (M)
Mammary carcinoma (M)
T cells Lung cancer (M)
Mammary carcinoma (M)
Breast carcinoma (M)
Colon adenocarcinoma (M)
Melanoma (M and H
phase I trial)
Lung cancer (M)
Colon carcinoma (M)
Melanoma (M)
Breast cancer (M)
Melanoma (M)
Neuroblastoma (H)
Ovarian carcinoma (M)
Colorectal carcinoma (M)
Melanoma (H)
CCL2, CCL3 (rCCL2
and/or rCCL3)
CCL5 (rCCL5, Ad-RANTES-E1A)
CCL19 (rCCL19)
CCL20 (rCCL20)
CCL21 (rCCL21, nanoparticles,
Ad-CCL21–transduced DC)
CXCL8 (rCXCL8)
CX3CL1 (rCX3CL1)
CXCR1 (adoptive
immunotherapy)
TIL
Macrophages, neutrophils
T cells, NK cells
CD4þ and CD8þ T cells,
NK cells
CD8þ T cells, NK cells
T cells DC
CD4, NK cells
CD8þ T cells, DC
Macrophage
Macrophage, T cells
Immune effector cells
Infiltrating cells
Lymphocyte-dependent
response
Unknown
Increase of immune cell
infiltration into tumors
Increase of tumor infiltration
by CD4þ and CD8þ T
cells, and neutrophils
Tumor-infiltrating T cells
Increase of immune cell
infiltration into tumors
T-cell proliferation, cytokine
secretion
APC maturation and T-cell
priming
Increase of tumor infiltration
by immune cells
Unknown
Lymphocyte-dependent
response
Lymphocyte-dependent
response
Immune response
Increase of TIL recruitment
into CXCL1 and CXCL8expressing tumors
Tumor regression
Tumor regression
Tumor regression
Tumor growth inhibition
Complete tumor
eradication
Tumor rejection
Tumor growth inhibition
Tumor regression
Tumor rejection
Tumor regression
Tumor regression
Treatment outcome
NOTE: Respective human chemokines, DC, or adenoviral vectors encoding human chemokines were injected directly at the tumor site.
Abbreviations: Ad, adenovirus; DC, dendritic cells; (H), human; (M), mouse; r: recombinant.
XCL1 (Ad-XCL1 þ IL-2 or
IL-12 or XCL1 þ gp100pulsed DC)
CCL22 (Ad-CCL22)
CCL16 (rCCL16, CCL16 fusion
protein: LEC-chTNT3)
Mouse (M) or Human (H)
tumor model
Human chemokines
(therapeutic approach)
Table 1. Experimental and clinical trials based on intratumoral delivery of human chemokines
(55)
(46)
(47)
(53)
(54)
(5)
(29)
(23)
(52)
(5)
(5)
(27)
(52)
(52)
(5)
References
Published OnlineFirst December 7, 2012; DOI: 10.1158/0008-5472.CAN-12-2027
Chemokines and the Antitumor Immune Response
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Franciszkiewicz et al.
cells through chemokine receptors relocalized at the immune
synapse (27).
Role of Chemokines in Shaping the Tumor
Microenvironment
The tumor microenvironment is characterized by chronic
inflammation with the presence of cytokines and chemokines,
the profile of which dictates neoplastic outcome (7). Indeed,
chemokines mediate accumulation of immunocompetent cells
and participate in shaping a tumor-promoting or -suppressive
microenvironment. CCR5 and CXCR3 predominate on Th1
cells, whereas Th2 cells preferentially express CCR3, CCR4, and
CCR8. At the tumor site, Th1 cells colocalize with macrophages
and neutrophils, enhancing the cell-mediated immune
response. In contrast, Th2-type inflammation is considered
to be protumoral and is associated with a poor prognosis (41).
Chemokine receptor patterns that guide CD8 T cells to
target tissues have not been studied as extensively as CD4 T
cells but seem to be similar. Upon antigen-reencounter, CD8 T
cells secrete inflammatory chemokines, such as CCL3 and
CCL5, which increase infiltration of neutrophils, monocytes,
and Th1 lymphocytes, and thus contribute to so-called autorecruitment of CTL, resulting in amplification of effector
responses. However, the protective activity of TIL is often
compromised by immunosuppressive tumor microenvironment components, including Treg cells. Treg can be actively
attracted to the tumor mostly via CCR4. Infiltration by Treg of
ovarian tumors producing high levels of CCL17 and CCL22
correlated with unfavorable prognosis (42). Treg cells,
recruited through CCL22-CCR4, can be activated in lymphoid
infiltrates surrounding breast tumors, leading to an adverse
clinical outcome (43). Other immunosuppressive cells participating in shaping the tumor microenvironment are myeloidderived suppressor cells (MDSC; Fig. 1). Once recruited within
tumors in a CCR2, CXCR4, or CXCR2-dependent manner,
MDSC have a significant effect on tumor progression, mainly
through suppression of antitumor effectors (44). Thus, by
determining the composition of cellular infiltrates, intratumoral chemokines continuously shape the tumor microenvironment and regulate the extent of antitumor immune
responses.
Chemokines in Cancer Immunotherapy
Strategies of chemokine–chemokine receptor–based tumor
immunotherapy are aimed at eradicating tumors by inhibiting
survival and metastasis of malignant cells. The overexpression
of chemokines at the tumor site usually resulted in infiltration
by host leukocytes; however, disease outcome was more divergent and related to the nature of the injected chemokines, the
subset of recruited immune cells and the tumor model (Table
1). In mice, intratumoral delivery of chemokines can induce
tumor suppression and immunity to subsequent tumor challenge through recruitment of dendritic cells, NK, and T cells (5).
However, the efficacy of such approaches seems limited in
humans (23). As chemokines are also responsible for attraction
of immunosuppressive cells, such as Treg cells, blocking the
activity of the host CCR5 has been proposed for improving the
potency of dendritic cell–based vaccines against melanoma
6330
Cancer Res; 72(24) December 15, 2012
(45). Combination of chemokines with cytokines for cancer
immunotherapy seems to deserve consideration. A combination of XCL1 and interleukin (IL)-2 has been reported to
provide enhanced and long-term antitumor immunity (46).
Other approaches to chemokine-based tumor immunotherapy include vaccination strategies with TAA. Despite a great
deal of effort, the rate of objective cancer regression in vaccinated patients has remained weak. Among the limitations of
such vaccines are the insufficient numbers of recruited effector
cells and their inappropriate activation in an immunosuppressive tumor microenvironment (1). In this context, manipulating the chemokine network may represent an attractive adjuvant strategy (Table 1). A vaccine based on XCL1- and IL-2–
secreting neuroblastoma cells induced an increase in T-cell
infiltration and resulted in complete or partial tumor remission in vaccinated patients (47). Adoptive immunotherapy is
currently one of the most promising approaches, with significant positive results in preclinical and clinical trials (48, 49).
The success of adoptive therapy depends on the optimal
selection and/or genetic engineering of antigen-specific cells,
induction of their proliferation while preserving effector functions, engraftment ability, and efficient homing to the tumor
(50, 51). Because recruitment of transfused lymphocytes at the
tumor site is one of the critical steps, intratumoral expression
of adequate chemokines represents one of the strategies for
improving adoptive immunotherapy. Moreover, redirecting
the migratory properties of adoptively transferred T cells
toward chemokine-secreting tumors can be achieved by genetic expression of appropriate chemokine receptors. Thus, the
intratumoral production of chemokines, which determine the
optimal CTL recruitment, is one of the key factors for efficient
antitumor responses. Any alteration can result in tumor evasion and represent one of the conceivable reasons for the
failure of adoptive transfer or vaccination-based immunotherapies (4).
Concluding Remarks
The success of cancer immunotherapeutic strategies
relies on the generation of efficacious effector mechanisms
associated with the presence of high-avidity tumor-specific
CTL. Chemokines contribute to induction of an effective
immune response, orchestrating distribution of its key cellular components, and delivering the generated effectors to
the target. It should, however, be noted that the chemokine–
chemokine receptor network is also implicated in immune
system homeostasis, thus limiting its manipulation in a
clinical setting. Despite these obstacles, intensified investigation of the role of chemokines in tumor immunosurveillance and immunosuppression may provide a gateway to
development of innovative and effective strategies for cancer
immunotherapy.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Authors' Contributions
Conception and design: K. Franciszkiewicz, M. Boutet, C. Combadiere, F.
Mami-Chouaib
Development of methodology: F. Mami-Chouaib
Cancer Research
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Published OnlineFirst December 7, 2012; DOI: 10.1158/0008-5472.CAN-12-2027
Chemokines and the Antitumor Immune Response
Acquisition of data (provided animals, acquired and managed patients,
provided facilities, etc.): F. Mami-Chouaib
Analysis and interpretation of data (e.g., statistical analysis, biostatistics,
computational analysis): F. Mami-Chouaib
Writing, review, and/or revision of the manuscript: K. Franciszkiewicz, A.
Boissonnas, M. Boutet, C. Combadiere, F. Mami-Chouaib
Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): K. Franciszkiewicz, F. Mami-Chouaib
Study supervision: F. Mami-Chouaib
Grant Support
This work was supported by grants from Institut National de la Sante et de la
Recherche Medicale (INSERM), the Association pour la Recherche sur le Cancer
(ARC), the Ligue contre le Cancer, and Institut National du Cancer. K. Franciszkiewicz was supported by a fellowship from the ARC and INCa.
Received May 21, 2012; revised September 13, 2012; accepted October 1, 2012;
published OnlineFirst December 7, 2012.
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Published OnlineFirst December 7, 2012; DOI: 10.1158/0008-5472.CAN-12-2027
Role of Chemokines and Chemokine Receptors in Shaping the
Effector Phase of the Antitumor Immune Response
Katarzyna Franciszkiewicz, Alexandre Boissonnas, Marie Boutet, et al.
Cancer Res 2012;72:6325-6332. Published OnlineFirst December 7, 2012.
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