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Suppressing MDSC Recruitment to the Tumor Microenvironment by Antagonizing CXCR2 to Enhance the Efficacy of Immunotherapy

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Myeloid-derived suppressor cells (MDSCs) are a heterogenous population of cells derived from immature myeloid cells. These cells are often associated with poor responses to cancer therapy, including immunotherapy, in a variety of tumor types. The C-X-C chemokine receptor 2 (CXCR2) signaling axis plays a key role in the migration of immunosuppressive MDSCs into the tumor microenvironment (TME) and the pre-metastatic niche. MDSCs impede the efficacy of immunotherapy through a variety of mechanisms. Efforts to target MDSCs by blocking CXCR2 is an active area of research as a method for improving existing and novel immunotherapy strategies. As immunotherapies gain approval for a wider array of clinical indications, it will become even more important to understand the efficacy of CXCR2 inhibition in combating immunotherapy resistance at different stages of tumor progression.
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cancers
Review
Suppressing MDSC Recruitment to the Tumor
Microenvironment by Antagonizing CXCR2 to Enhance the
Efficacy of Immunotherapy
Kennady Bullock 1and Ann Richmond 1, 2, *


Citation: Bullock, K.; Richmond, A.
Suppressing MDSC Recruitment to
the Tumor Microenvironment by
Antagonizing CXCR2 to Enhance the
Efficacy of Immunotherapy. Cancers
2021,13, 6293. https://doi.org/
10.3390/cancers13246293
Academic Editor: Bernhard Moser
Received: 30 October 2021
Accepted: 9 December 2021
Published: 15 December 2021
Publisher’s Note: MDPI stays neutral
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Copyright: © 2021 by the authors.
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Attribution (CC BY) license (https://
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4.0/).
1Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA;
kennady.k.bullock@vanderbilt.edu
2Department of Veterans Affairs, Tennessee Valley Healthcare System, 432 PRB, 2220 Pierce Ave,
Nashville, TN 37232, USA
*Correspondence: ann.richmond@vanderbilt.edu
Simple Summary:
While the development of immunotherapy has greatly advanced cancer treat-
ment, many patients do not benefit from immunotherapy. Numerous strategies have been developed
to improve response to immunotherapy across cancer types, including blocking the activity of im-
munosuppressive immune cells, cytokines, and signaling pathways that are linked to poor responses.
Myeloid-derived suppressor cells (MDSCs) are associated with poor responses to immunotherapy,
and the chemokine receptor, CXCR2, is involved in recruiting MDSCs to the tumor. In this review, we
present studies that explore the potential of inhibiting MDSCs through blocking CXCR2 as a strategy
to enhance response to existing and novel immunotherapies.
Abstract:
Myeloid-derived suppressor cells (MDSCs) are a heterogenous population of cells derived
from immature myeloid cells. These cells are often associated with poor responses to cancer therapy,
including immunotherapy, in a variety of tumor types. The C-X-C chemokine receptor 2 (CXCR2)
signaling axis plays a key role in the migration of immunosuppressive MDSCs into the tumor mi-
croenvironment (TME) and the pre-metastatic niche. MDSCs impede the efficacy of immunotherapy
through a variety of mechanisms. Efforts to target MDSCs by blocking CXCR2 is an active area of
research as a method for improving existing and novel immunotherapy strategies. As immunothera-
pies gain approval for a wider array of clinical indications, it will become even more important to
understand the efficacy of CXCR2 inhibition in combating immunotherapy resistance at different
stages of tumor progression.
Keywords:
myeloid-derived suppressor cells (MDSCs); CXCR2; immunotherapy resistance; immune
checkpoint inhibitors
1. Introduction
According to the concept of cancer immune editing, tumor cells progress through three
stages of interaction with the immune system: elimination, equilibrium, and escape [
1
].
Therefore, clinically diagnosable tumors have evolved to bypass the immune system’s
natural, protective mechanisms. Immunotherapy strategies, including immune checkpoint
inhibitors, cancer vaccines, adoptive T-cell therapy, and genetically modified immune cells,
seek to activate the patient’s immune system against tumor cells that have progressed
through the escape phase [
2
]. FDA-approved immune checkpoint inhibitors include
antibodies against the following checkpoint proteins: cytotoxic T-lymphocyte-associated
protein 4 (CTLA4), programmed cell death protein 1 (PD1), and programmed death-ligand
1 (PD-L1). Immune checkpoint inhibitors have greatly expanded treatment options for
patients with late-stage, metastatic disease [
3
], and are currently being investigated as
treatment strategies in the neoadjuvant setting [
4
]. Despite long-term survival benefits in
Cancers 2021,13, 6293. https://doi.org/10.3390/cancers13246293 https://www.mdpi.com/journal/cancers
Cancers 2021,13, 6293 2 of 14
some patients, a large patient population remains that either does not respond to immune
checkpoint inhibitors or develops resistance after an initial period of response, necessitating
the development of treatment strategies that overcome resistance. As immunotherapy
expands for the treatment of earlier-stage tumors, additional markers and mechanisms
of resistance will likely emerge. Resistance to immunotherapy can occur via tumor cell-
extrinsic and/or tumor cell-intrinsic mechanisms [
5
], and targeting MDSCs through CXCR2
inhibition is an emerging strategy to counteract both mechanisms of resistance.
2. The Role of MDSCs in the Establishment of an Immunosuppressive Niche
Tumor cell-extrinsic mechanisms of immunotherapy resistance include low infiltration
of tumor antigen-specific T cells and the presence of immunosuppressive cells such as
MDSCs and tumor-associated macrophages (TAMs) [
6
]. Elevated numbers of MDSCs are
associated with poor response to therapy, including, immunotherapy across several tumor
types [
7
9
]. High numbers of MDSCs in the peripheral blood were associated with poor
overall survival in a phase I/II study of melanoma patients treated with anti-PD1 therapy
after progressing on anti-CTLA4 therapy [
10
]. Similarly, melanoma patients being treated
with anti-CTLA4 with lower levels of MDSCs following their first infusion had increased
overall survival compared to patients with higher circulating MDSCs [11].
Once in the tumor microenvironment (TME), MDSCs contribute to immune sup-
pression through a variety of mechanisms including production of inducible nitric ox-
ide synthase (iNOS), arginase 1 (ARG1), transforming growth factor-beta (TGF
β
), IL-10,
cyclooxygenase-2 (COX2), and indoleamine 2,3-dioxygenase (IDO) [
12
]. MDSCs can also
suppress CD8+ T-cell activity through the expression of Fas-ligand, which interacts with
Fas expressed on tumor-infiltrating lymphocytes (TILs) to induce TIL apoptosis [
13
]. Block-
ing this interaction with soluble Fas-Fc restored sensitivity to immune checkpoint blockade
therapy in a mouse model of melanoma [
13
]. Additionally, MDSCs help recruit other im-
munosuppressive cells such as TAMs. In a murine model of prostate cancer, administration
of a CXCR2 antagonist or infusion of bone marrow-derived CXCR2 KO macrophages led
to a reduction in tumor growth and a reprogramming of TAMs to a pro-inflammatory, M1
phenotype [
14
]. As well as promoting immunosuppression, MDSCs are also involved in
various aspects of tumorigenesis including epithelial to mesenchymal transition (EMT) [
15
],
angiogenesis [
16
], and establishment of the pre-metastatic niche [
17
]. Due to their multi-
faceted roles in immunosuppression, promotion of tumor growth, and treatment resistance,
MDSCs are a desirable therapeutic target.
MDSC Classifications
There are two main classifications of MDSCs, granulocytic/polymorphonuclear (G-
MDSCs/PMN-MDSCs) and monocytic (M-MDSCs), each with distinct surface protein
expression profiles. The terms G-MDSCs and PMN-MDSCs may be used interchange-
ably. Mouse markers of G-MDSCs and M-MDSCs include CD11b
+
Ly6G
+
Ly6C
lo
and
CD11b
+
Ly6G
Ly6C
hi
, respectively, while human G-MDSCs can be defined as CDllb
+
CD14
CD15
+
CD66
+
Lox-1
+
and human M-MDSCs are defined as CD14
+
CD15
HLA
DR
/l0
[
8
].
Both types of MDSCs emerge from common myeloid progenitor (CMP) cells, but M-MDSCs
more closely follow the differentiation pathway of monocytes whereas G-MDSCs more
closely follow the differentiation pathway of granulocytes [
18
,
19
] (Figure 1). In mouse
models, it is difficult to distinguish M-MDSCs from monocytes and G-MDSCs from gran-
ulocytes due to the lack of unique surface markers and the reliance on functional assays
to identify MDSCs. However, CD14 was recently described as a marker to distinguish
PMN-MDSCs from classical neutrophils in tumor-bearing mice [
20
]. In contrast, human
M-MDSCs and G-MDSCs are more readily distinguished from monocytes and granu-
locytes. Human M-MDSCs can be distinguished from monocytes by the expression of
HLA-DR [
12
], and Lectin type oxidized receptor I (LOX-1) can be used to distinguish PMN-
MDSCs from neutrophils both in peripheral blood and in tumor tissue [
21
]. Furthermore,
G-MDSCs are lower density cells and can be separated from neutrophils by Ficoll gradient
Cancers 2021,13, 6293 3 of 14
centrifugation of peripheral blood mononuclear cells (PMBCs) [
22
]. G-MDSCs are also
very similar to another cell type—the tumor-associated neutrophil (TAN). TANs can be
polarized and have been described as N1 TANs that have anti-tumorigenic activity, and
N2 TANs that are pro-tumorigenic [
23
]. There is much debate surrounding the distinc-
tions, if any, between G-MDSCs and N2 TANs [
24
]. M-MDSCs can further differentiate
into tumor associate macrophages (TAMs) and inflammatory dendritic cells in the tumor
microenvironment
[2527]
, while G-MDSCs are a differentiated, pathologically activated
cell type [
28
]. A small population of M-MDSCs was initially postulated to be able to dif-
ferentiate into G-MDSCs through downregulation of the retinoblastoma 1 (Rb1) gene [
29
];
however, this precursor population was later identified as monocyte-like precursors of
granulocytes (MLPGs), and MLPGs contributed to up to 50% of the total G-MDSCs in some
mouse tumor models [30].
Cancers 2021, 13, x 3 of 14
monocytes and granulocytes. Human M-MDSCs can be distinguished from monocytes by
the expression of HLA-DR [12], and Lectin type oxidized receptor I (LOX-1) can be used
to distinguish PMN-MDSCs from neutrophils both in peripheral blood and in tumor tis-
sue [21]. Furthermore, G-MDSCs are lower density cells and can be separated from neu-
trophils by Ficoll gradient centrifugation of peripheral blood mononuclear cells (PMBCs)
[22]. G-MDSCs are also very similar to another cell type—the tumor-associated neutrophil
(TAN). TANs can be polarized and have been described as N1 TANs that have anti-tu-
morigenic activity, and N2 TANs that are pro-tumorigenic [23]. There is much debate sur-
rounding the distinctions, if any, between G-MDSCs and N2 TANs [24]. M-MDSCs can
further differentiate into tumor associate macrophages (TAMs) and inflammatory den-
dritic cells in the tumor microenvironment [25–27], while G-MDSCs are a differentiated,
pathologically activated cell type [28]. A small population of M-MDSCs was initially pos-
tulated to be able to differentiate into G-MDSCs through downregulation of the reti-
noblastoma 1 (Rb1) gene [29]; however, this precursor population was later identified as
monocyte-like precursors of granulocytes (MLPGs), and MLPGs contributed to up to 50%
of the total G-MDSCs in some mouse tumor models [30].
Figure 1. Developmental lineage of MDSCs. M-MDSCs and G-MDSCs arise from a common mye-
loid progenitor (CMP) and a granulocyte/monocyte progenitor (GMP). GMP cells differentiate into
one of three cell types: monocyte-dendritic cell progenitor (MDP), granulocyte progenitor (GP), or
monocyte-like precursor of granulocytes (MLPG) [18,19]. M-MDSCs are derived from MDPs and
can further differentiate into TAMs or dendritic cells [25]. G-MDSCs can be derived from either
MLPGs or GPs and are considered a fully differentiated cell type, distinct from neutrophils that are
also derived from GP cells [30]. Adapted from Figure 1 Gabrilovich et al. 2012 Nat. Rev. Immunol.
3. The Role of CXCR2 in Tumor Cell-Intrinsic Mechanisms of Immunotherapy Re-
sistance
In a physiological setting, CXCR2 is primarily expressed by neutrophils and is essen-
tial for the recruitment of leukocytes to sites of inflammation, infection, or tissue damage
[31]. In the context of cancer, CXCR2 plays a major role in the recruitment of MDSCs to
the TME [32]. CXCR2 is a G protein-coupled receptor (GPCR) that signals through Gi-
coupled mechanisms, and the crystal structure of CXCR2 bound to an antagonist was re-
cently determined [33]. CXCR2 activation can also occur via the formation of heterodimers
with the atypical chemokine receptor CCRL2, and this is involved in neutrophil recruit-
ment to sites of inflammation [34]. CXCR1 is a GPCR closely related to CXCR2 that is
involved in neutrophil and MDSC chemotaxis in humans; however, a role for mouse
Figure 1.
Developmental lineage of MDSCs. M-MDSCs and G-MDSCs arise from a common myeloid
progenitor (CMP) and a granulocyte/monocyte progenitor (GMP). GMP cells differentiate into
one of three cell types: monocyte-dendritic cell progenitor (MDP), granulocyte progenitor (GP), or
monocyte-like precursor of granulocytes (MLPG) [
18
,
19
]. M-MDSCs are derived from MDPs and can
further differentiate into TAMs or dendritic cells [
25
]. G-MDSCs can be derived from either MLPGs
or GPs and are considered a fully differentiated cell type, distinct from neutrophils that are also
derived from GP cells [30]. Adapted from Figure 1Gabrilovich et al. 2012 Nat. Rev. Immunol.
3. The Role of CXCR2 in Tumor Cell-Intrinsic Mechanisms of
Immunotherapy Resistance
In a physiological setting, CXCR2 is primarily expressed by neutrophils and is essential
for the recruitment of leukocytes to sites of inflammation, infection, or tissue damage [
31
].
In the context of cancer, CXCR2 plays a major role in the recruitment of MDSCs to the
TME [
32
]. CXCR2 is a G protein-coupled receptor (GPCR) that signals through G
i
-coupled
mechanisms, and the crystal structure of CXCR2 bound to an antagonist was recently
determined [
33
]. CXCR2 activation can also occur via the formation of heterodimers with
the atypical chemokine receptor CCRL2, and this is involved in neutrophil recruitment to
sites of inflammation [
34
]. CXCR1 is a GPCR closely related to CXCR2 that is involved in
neutrophil and MDSC chemotaxis in humans; however, a role for mouse CXCR1 involve-
ment in neutrophil or MDSC recruitment has not been established [
35
], [
36
]. In humans and
mice, CXCR2 is expressed by tumor cells, neutrophils, mast cells, monocytes, macrophages,
endothelial cells, muscle cells, and epithelial cells [
31
]. CXCR2 is also expressed on MDSCs
and was identified as part of an MDSC gene signature in a scRNAseq analysis of MDSCs
from tumors and spleens of MMTV-PYMT mice [
37
]. The major CXCR2 ligands associated
Cancers 2021,13, 6293 4 of 14
with MDSC chemotaxis are CXCL5, CXCL2, CXCL1, and CXCL8 (IL-8) [
38
] (Figure 2). It is
important to note, however, that while CXCL8 is a major CXCR2 ligand in humans, it is not
expressed in mice [
31
]. Tumor cell-intrinsic mechanisms of immunotherapy resistance in-
clude alterations in tumor cell signaling pathways that alter interactions with immune cells
in the TME. Increased tumor cell secretion of CXCR2 ligands can contribute to resistance
to immunotherapy. In studies using 3D cell cultures and the 4T1 mouse model of breast
cancer, tumor-secreted CXCR1/2 ligands induced the formation of neutrophil extracellular
traps (NETs) which block the contact of cytotoxic T cells and NK cells with tumor cells.
Inhibition of this process with protein arginase deiminase 4 (PAD4) inhibitors led to an
increase in sensitivity to the combination treatment of anti-PD1 + anti-CTLA4 [39].
Cancers 2021, 13, x 4 of 14
CXCR1 involvement in neutrophil or MDSC recruitment has not been established [35],
[36]. In humans and mice, CXCR2 is expressed by tumor cells, neutrophils, mast cells,
monocytes, macrophages, endothelial cells, muscle cells, and epithelial cells [31]. CXCR2
is also expressed on MDSCs and was identified as part of an MDSC gene signature in a
scRNAseq analysis of MDSCs from tumors and spleens of MMTV-PYMT mice [37]. The
major CXCR2 ligands associated with MDSC chemotaxis are CXCL5, CXCL2, CXCL1, and
CXCL8 (IL-8) [38] (Figure 2). It is important to note, however, that while CXCL8 is a major
CXCR2 ligand in humans, it is not expressed in mice [31]. Tumor cell-intrinsic mecha-
nisms of immunotherapy resistance include alterations in tumor cell signaling pathways
that alter interactions with immune cells in the TME. Increased tumor cell secretion of
CXCR2 ligands can contribute to resistance to immunotherapy. In studies using 3D cell
cultures and the 4T1 mouse model of breast cancer, tumor-secreted CXCR1/2 ligands in-
duced the formation of neutrophil extracellular traps (NETs) which block the contact of
cytotoxic T cells and NK cells with tumor cells. Inhibition of this process with protein
arginase deiminase 4 (PAD4) inhibitors led to an increase in sensitivity to the combination
treatment of anti-PD1 + anti-CTLA4 [39].
Figure 2. Immunosuppressive cells in the TME. The CXCR2 ligands, CXCL5, CXCL2, CXCL1, and
CXCL8 attract G-MDSCs, M-MDSCs, TANs to the TME where they establish an immunosuppres-
sive niche [38]. M-MDSCs can further differentiate into TAMs and inflammatory dendritic cells [25].
Both M-MDSCs and G-MDSCs inhibit the effector functions of T cells through mechanisms such as
the secretion of iNOS, ARG1, TGFβ, IL-10, and COX2 [12]. TANS can either have anti-tumor, N1
properties or pro-tumor, N2 properties [23]. The role of TANs in the TME is a source of ongoing
research. Adapted from Figure 1 Raman et al. 2007 Cancer Letters.
4. Expression of CXCR2 and CXCR2 Ligands Is Associated with Poor Response to
Therapy
CXCR2 and CXCR2 ligands are markers of poor prognosis in several tumor types. A
meta-analysis of 4012 patients with solid tumors from 21 different studies found that
CXCR2 expression was predictive of poor prognosis of patients with hepatocellular carci-
noma, gastric cancer, or esophageal cancer [40]. Similarly, CXCR2 expression was identi-
fied as a poor prognostic marker in lung cancer [41], pancreatic ductal adenocarcinoma
[42], and colorectal cancer [43]. Elevated serum levels of the CXCR2 ligands CXCL1 and
CXCL2 correlated with increased intra-tumoral MDSC infiltration and reduced overall
survival in a cohort of ovarian cancer patients [44], while elevated serum CXCL8 was as-
sociated with metastasis and reduced overall survival in pediatric patients with rhabdo-
myosarcoma [45]. CXCL8 in particular has been found to associate with poor response to
Figure 2.
Immunosuppressive cells in the TME. The CXCR2 ligands, CXCL5, CXCL2, CXCL1, and CXCL8 attract G-MDSCs,
M-MDSCs, TANs to the TME where they establish an immunosuppressive niche [
38
]. M-MDSCs can further differentiate
into TAMs and inflammatory dendritic cells [
25
]. Both M-MDSCs and G-MDSCs inhibit the effector functions of T cells
through mechanisms such as the secretion of iNOS, ARG1, TGF
β
, IL-10, and COX2 [
12
]. TANS can either have anti-tumor,
N1 properties or pro-tumor, N2 properties [
23
]. The role of TANs in the TME is a source of ongoing research. Adapted from
Figure 1Raman et al. 2007 Cancer Letters.
4. Expression of CXCR2 and CXCR2 Ligands Is Associated with Poor Response
to Therapy
CXCR2 and CXCR2 ligands are markers of poor prognosis in several tumor types. A
meta-analysis of 4012 patients with solid tumors from 21 different studies found that CXCR2
expression was predictive of poor prognosis of patients with hepatocellular carcinoma, gas-
tric cancer, or esophageal cancer [
40
]. Similarly, CXCR2 expression was identified as a poor
prognostic marker in lung cancer [
41
], pancreatic ductal adenocarcinoma [
42
], and colorec-
tal cancer [
43
]. Elevated serum levels of the CXCR2 ligands CXCL1 and CXCL2 correlated
with increased intra-tumoral MDSC infiltration and reduced overall survival in a cohort of
ovarian cancer patients [
44
], while elevated serum CXCL8 was associated with metastasis
and reduced overall survival in pediatric patients with rhabdomyosarcoma [
45
]. CXCL8
in particular has been found to associate with poor response to immunotherapy [
46
,
47
].
A retrospective analysis of 1344 patients across four phase-3 clinical trials, encompassing
patients receiving treatment for melanoma, NSCLC, and renal cell carcinoma found an
association between serum CXCL8 levels and poor response to immune checkpoint inhibi-
tion [
48
]. Interestingly, high expression of CXCR2 was associated with higher-grade tumors
but longer relapse-free survival and higher TIL infiltration in a cohort of triple-negative
breast cancer patients treated with adjuvant chemotherapy [
49
]. The cell-type specificity
of CXCR2 expression is important when considering correlations with clinical outcomes,
and they found that CXCR2 expression by immunohistochemistry primarily overlapped
with the neutrophil markers CDllb and CD66b [
49
]. It is possible that these neutrophils
Cancers 2021,13, 6293 5 of 14
were phenotypically N1, anti-tumor and that the presence of these TANs contributed to the
longer relapse-free survival observed in this patient cohort. Several other studies identified
CXCR2 as a key player in establishing the metastatic niche of breast cancer [
14
,
44
,
45
]. In
the 4T1 murine tumor model of triple-negative breast cancer, CXCR2+ MDSCs are elevated
in lung and lymph node metastases [
15
,
50
]. Bone is one of the most common sites of breast
cancer metastasis, and in studies using ex vivo cultures of mouse long bones co-cultured
with PyMT tumor cells, CXCR2 drove tumor cell colonization in the bone explants [
51
].
Furthermore, CXCR2 was expressed on G-MDSCs in the tumor microenvironment in the
E0771-luciferase murine model of triple-negative breast cancer [52].
5. CXCR2 Inhibition May Enhance the Efficacy of Existing Immunotherapy Agents
Given the role that CXCR2 plays in recruiting MDSCs to the tumor microenvironment,
CXCR2 inhibition is a promising strategy to relieve MDSC-mediated immunosuppression
and improve the effectiveness of existing immunotherapies. As immunotherapies gain
approval for a wider variety of cancer types and stages, it will become more important
to better understand the particular indications for which CXCR2 inhibition may provide
synergistic benefit when paired with immunotherapy. The immunologic milieu of tumors at
the primary site differs from tumors at metastatic sites, suggesting that immunomodulatory
strategies can have divergent effects on primary versus metastatic tumors [
53
]. CXCR2 is a
well-studied player in the establishment in the metastatic niche in a variety of cancers [
54
].
In a study of surgical specimens from patients with colorectal cancer, CXCR2 expression
was significantly increased in tumors from patients who had distant metastases in the lung
or liver compared to patients with localized disease [
55
]. In a murine model of breast cancer
metastasis, lungs from tumor-bearing, myeloid-specific CXCR2 KO mice had a decreased
M2 macrophage population and an increased CD8+ T-cell population as compared to
WT controls [
56
]. Furthermore, myeloid-specific CXCR2 KO mice displayed decreased
intra-tumor infiltration of MDSCs both in models of breast cancer and melanoma, and those
remaining MDSCs were less functional [
56
]. The role of CXCR2 in promoting metastasis
alongside the evidence of elevated CXCR2 in metastatic disease compared to localized
disease may suggest that patients with metastatic disease will benefit from a combination
of immunotherapy and CXCR2 antagonism. In a murine model of melanoma, inhibiting
CXCR2 after surgical resection of the primary tumor significantly extended survival and
reduced the incidence of distant metastases [
57
]. In the spontaneous KPC mouse model of
pre-invasive pancreatic cancer, there were no differences in overall or tumor-free survival
between wild-type and CXCR2
/
mice; however, genetic deletion of CXCR2 significantly
reduced metastasis in mice greater than 10 weeks old [
42
]. Pharmacological inhibition of
CXCR2 similarly reduced metastasis, suggesting CXCR2 inhibition may be more effective
in later-stage tumors after surgical resection of the primary tumor [42].
5.1. CXCR2 Antagonism in Combination with Immune Checkpoint Inhibitors
Several pre-clinical studies have examined the synergism of CXCR2 antagonism with
immune checkpoint inhibitors and other immunotherapy agents. In studies using the
MOC1 (murine oral cancer 1) model, single-agent treatment with either the CXCR1/2
antagonist, SX-682, or PD1-mAb had no significant effect on tumor growth or survival, but
combination treatment with SX-682 and PD1-mAb significantly reduced tumor growth,
improved survival, and caused complete tumor rejection in 20% of mice [
58
]. In a differ-
ent study using the MOC1 tumor model, depletion of G-MDSCs with a Ly6G+ mAb in
combination with anti-CTLA4 led to tumor rejection in 11/11 mice, whereas anti-CTLA4
treatment led to tumor rejection in 5/11 mice [
59
], providing further evidence for the
efficacy of strategies that target MDSCs to improve immunotherapy responses. In a PD1-
mAb-resistant mouse model of pancreatic cancer, pharmacological inhibition of CXCR2
synergized with anti-PD1 therapy to significantly extend survival, while genetic deletion
or inhibition of CXCR2 increased T-cell infiltration into the TME. These effects were depen-
dent on CXCR2 expression on Ly6G+ cells, as Ly6G depletion abrogated these effects [
42
].
Cancers 2021,13, 6293 6 of 14
However, it is important to consider that a Ly6G antibody will deplete neutrophils as well
as G-MDSCs in this experimental design. Combination treatment with SX-682 and anti-PD1
significantly reduced tumor burden compared to both vehicle control and single-agent
treatment groups in a murine model of melanoma [
56
]. Similarly, in a murine model of
rhabdomyosarcoma (RMS), treatment with an anti-CXCR2 antibody sensitized tumors to
anti-PD1 treatment [
45
]. In addition to these promising pre-clinical studies, there are ongo-
ing clinical studies examining CXCR2 antagonism in combination with immune checkpoint
inhibitors; SX-682 in combination with pembrolizumab (anti-PD1) for the treatment of
metastatic melanoma (NCT03161431), SX-682 in combination with nivolumab (anti-PD1)
for metastatic pancreatic ductal adenocarcinoma (NCT04477343) (Table 1).
Table 1. Ongoing oncology clinical trials targeting CXCR2.
Combination Drug Name Indication Phase Clinical Trial ID
CXCR2i + hormonal therapy AZD5069+
enzalutamide
Metastatic castration-resistant
prostate cancer I/II NCT03177187
CXCR1/2i + anti-PD1 SX-682+ nivolumab Metastatic pancreatic ductal
adenocarcinoma I NCT04477343
CXCR1/2i + anti-PD1 SX-682 + nivolumab
RAS-mutated, MSS
unresectable or metastatic
colorectal cancer
Ib/II NCT04599140
CXCR1/2i + anti-PD1 SX-682+
pembrolizumab Metastatic melanoma I NCT03161431
CXCR2-transduced autologous
TILs +
IL-2 + chemotherapy
CXCR2-transduced
TILs + aldesleukin +
cyclophosphamide and
fludarabine phosphate
Metastatic melanoma I/II NCT01740557
Single-agent CXCR1/2i SX-682 Myelodysplastic syndromes I NCT04245397
Clinical trial information from clinicaltrials.gov (accessed on 1 December 2021).
5.2. CXCR2 Antagonism in Combination with Other Immunotherapy Agents
Relatively few studies have examined the effects of CXCR2 antagonism in combination
with immunotherapy agents other than checkpoint inhibitors. In a study using the murine
oral cancer 2 (MOC2) model, administration of the CXCR1/2 small-molecule inhibitor,
SX-682, inhibited MDSC accumulation in the tumor and enhanced the efficacy of NK cell-
based adoptive cell transfer therapy [
60
]. CXCR2 antagonism was tested in combination
with immunotherapy consisting of adenovirus encoded TNF-related apoptosis ligand
(TRAIL) plus TLR9 agonist, CpG, oligonucleotide (AdT + CpG) in a murine model of
breast cancer. Interestingly, this combination provided benefit for obese animals, but not
for lean animals [
52
]. Obese mice were found to have an increase in FasL+ G-MDSCs,
which mediated apoptosis of CD8 T cells, as well as an increase in CXCR2 ligands. The
obesity-associated increase in CXCR2 ligands relative to the lean state [
61
], likely explains
why the obese mice were more responsive to CXCR2 inhibitor treatment. This suggests the
interesting possibility that patients with higher levels of CXCR2 ligands may respond better
to CXCR2 inhibition. In another study investigating the efficacy of dendritic cell vaccines
in a murine model of glioma, treatment with a CXCR2 neutralizing antibody reversed the
survival benefits seen with the vaccine [
62
]. The deleterious effects of blocking CXCR2 in
this instance, however, were due to the role that CXCR2 plays in driving the migration of
the modified dendritic cells to their therapeutic target. Thus, these data suggest that some
combinatorial therapies using CXCR2 antagonists will not be beneficial. As the selection of
available immunotherapy strategies widens, it will be important to explore whether the
benefits of CXCR2 antagonism will overcome resistance to other types of immunotherapies
in pre-clinical models.
Cancers 2021,13, 6293 7 of 14
6. Novel CXCR2-Based Immunotherapy Strategies
Blocking CXCR2 with small-molecule antagonists is one strategy to enhance the
efficacy of immunotherapy for clinical benefit; hijacking the functions of CXCR2 by driving
effector immune cells to express CXCR2 is another. The production of CXCR2 ligands
in the TME drives the recruitment of CXCR2-expressing cells into the tumor [
63
]. This
finding has important implications for the development of novel immunotherapy strategies.
CXCR2-modified chimeric antigen receptor T cells (CAR T cells) are under development to
enhance intra-tumoral T-cell infiltration [
64
66
]. CAR T-cell therapy has found its greatest
successes in the treatment of hematological malignancies, but successful intra-tumoral
infiltration of CAR T cells is the major limiting factor prohibiting the advancement of CAR
T-cell therapies in solid malignancies [
66
]. In a murine model of hepatocellular carcinoma,
treatment with CXCR2-modified CAR T cells significantly reduced tumor burden and
enhanced intra-tumoral T-cell infiltration [65]. In mouse xenograft models of ovarian and
pancreatic cancer, administration of CAR T cells engineered to co-express
α
v
β
6 integrin
and CXCR2 significantly reduced tumor growth [
64
]. In addition to these promising pre-
clinical studies, CXCR2-transduced autologous tumor-infiltrating lymphocytes are under
clinical investigation in patients with metastatic melanoma (Table 1). Additionally, there
are ongoing efforts to target CXCR2+ positive cells using CXCL5-modified nanoparticles
to deliver drug [
67
]. Natural killer (NK) cells are another effector immune cell type that
can have direct cytotoxic activities against tumor cells [
68
]. Primary NK cells from blood
and tumor biopsies from patients with renal cell carcinoma engineered ex vivo to express
CXCR2, showed enhanced migratory capabilities
in vitro
[
69
]. Driving effector cells such
as NK cells and T cells to express CXCR2 is a novel strategy for increasing the infiltration
of anti-tumor immune cells to the TME.
7. Clinical Status and Concerns of CXCR2 Antagonists
CXCR2 antagonists are under investigation as anti-inflammatory therapeutics in a
variety of disease states including chronic obstructive pulmonary disorder (COPD), type I
diabetes, rheumatoid arthritis, ulcerative colitis, and cancer [
70
]. The CXCR1/2 inhibitor,
reparixin, showed promise in a window-of-opportunity clinical trial for HER-2-negative
breast cancer. Reparaxin was safe, well-tolerated, and caused a reduction in cancer stem
cells in patient tumors [
71
]. A phase 1b trial in patients with metastatic breast cancer found
reparaxin to be safe in combination with paclitaxel [
72
]. When reparaxin was investigated
in combination with paclitaxel as a frontline treatment for metastatic triple-negative breast
cancer in a phase 2 trial; however, the primary endpoint of prolonged progression-free
survival was not met [
73
]. While there are no CXCR2-targeted drugs currently approved
for use in cancer treatment, other CXCR2 antagonists are in various stages of clinical
development (Table 1).
Clinical concerns with targeting CXCR2 include unwanted effects on other cell types
as well as the development of resistance mechanisms. The goal of CXCR2 antagonism
may be to target immunosuppressive cells in the TME, however expression of CXCR2 is
not limited to MDSCSs. CXCR2 is expressed by a variety of other cell types including
endothelial cells, epithelial cells, macrophages, and mast cells [
31
], and the potential off-
target effects on these other cell types necessitate further study. The impact of CXCR2
inhibition on the innate effector functions of neutrophils is a well-studied side effect. A
phase II clinical study of the CXCR2 antagonist, SCH527123, was discontinued due to
neutropenia in healthy subjects [74]. A second CXCR2 antagonist, AZD5069, was studied
in patients with COPD. Findings were more promising in that absolute blood neutrophil
counts were reduced in the first 24 h of treatment, but this was reversible upon treatment
cessation [
75
]. Moreover, in studies examining the effects of CXCR2 antagonists on the
function of neutrophils in blood from healthy patients, it was found that despite transient
decreases in neutrophil numbers, key antimicrobial functions such as phagocytosis and
oxidative burst were unaffected [
76
]. Similarly, CXCR2 inhibition did not affect B-cell
responses or cell-mediated immunity [
77
]. These studies provide evidence to support the
Cancers 2021,13, 6293 8 of 14
safety of CXCR2 antagonism, as transient decreases in total neutrophil counts may occur,
but the functionality of the neutrophils is unaffected.
It is important to consider that inhibition of neutrophil recruitment may have both
positive and negative effects in the context of cancer treatment. Neutrophils are recruited
to sites of inflammation, and there is evidence to suggest that neutrophils are capable of as-
suming anti-tumor N1 properties, particularly in the instance of early-stage disease [
78
,
79
].
In other instances, neutrophils can exhibit N2 phenotypes and promote tumor growth [
23
].
Recruitment of both N1 and N2 TANs will likely be altered with CXCR2 antagonism. A high
neutrophil-to-lymphocyte ratio in peripheral blood correlates with poor overall survival
across several solid tumor types [
80
]. However, neutrophil content in the peripheral blood
may not be reflective of neutrophils in the TME. TANs isolated from early-stage human
lung tumors exhibited an immune-activated phenotype and stimulated T-cell responses
in vitro
, suggesting that early-stage TANs possess anti-tumor functions [
81
]. Neutrophil
recruitment to the lung prevented the establishment of lung metastases in a NOD/SCID
mouse model using human renal cell carcinoma (RCC) cell lines [
82
]. Furthermore, poorly
metastatic human RCC cell lines exhibited increased secretion of the neutrophil recruiting
chemokines, CXCL5 and IL-8, compared to highly metastatic cell lines. Although there
are conflicting results regarding the pro- and anti-tumor functions of neutrophils, this
may be largely due to discrepancies in nomenclature and inconsistencies in distinguishing
G-MDSCs from N2 TANs. Blocking CXCR2 in early-stage disease may prevent the recruit-
ment of anti-tumor neutrophils, but the effect of CXCR2 inhibition on TAN phenotypes
necessitates further study and may vary depending upon the proportion of N1 versus N2
TANs in the TME.
Another clinical concern with blocking CXCR2 is the development of resistance mech-
anisms such as a compensatory increase in CXCR2 ligands which may cause an aggerated
inflammatory response. Breast cancer cell lines treated with the CXCR2 antagonist ex-
hibited an increase in CXCL2 as a resistance mechanism [
83
]. In a follow-up study, it
was found that treatment with a CXCR2 antagonist also caused an increase in CXCL1,
but that this rebound increase in CXCR2 ligands could be prevented by treatment with
PKC agonists including bryostatin I, FR236924, or Roy-bz [
84
]. However, this is not yet
a viable solution to treatment resistance, as there currently are no clinically approved
PKC agonists. Compensatory mechanisms in response to CXCR2 blockade were further
studied in a CXCR2 knockout (KO) mouse model. Unexpectedly, KO mice displayed an
exaggerated inflammatory response, accompanied by significantly higher levels of CXCL1
in the skin following application of the inflammatory stimulus, tetradecanoyl phorbol
13-acetate (TPA) [
85
]. The studies using CXCR2 KO mice emphasize the importance of
potential compensatory inflammatory pathways that may be activated when CXCR2 is tar-
geted pharmacologically. This is especially important to consider when combining CXCR2
antagonism with immunotherapy as immune-related toxicities and hyperinflammatory
responses are frequent reasons for the discontinuation of immunotherapies in patients [
86
].
8. Additional Strategies to Target MDSC Recruitment
Additional pathways beyond the CXCR2 signaling axis are involved in the recruitment
of MDSCs and can be targeted pharmacologically in combination with CXCR2 antagonists
and/or immunotherapy. One such axis involved in the recruitment of MDSCs is the colony-
stimulating factor-1 (CSF1)/colony-stimulating factor-1 receptor (CSF-1R) axis [
87
]. In a
murine orthotopic model of lung cancer, mice treated with a CSF1R inhibitor exhibited
increased intra-tumoral G-MDSCs, and this was found to be caused by increased secretion
of CXCL1 by cancer-associated fibroblasts (CAFs). Combined treatment with a CSF1R
inhibitor and a CXCR2 antagonist led to a significant reduction in tumor growth that was
further enhanced by the addition of anti-PD1 [
88
]. In a murine model of melanoma, CSF-
1R blockade successfully depleted MDSCs and also re-sensitized the tumors to therapies
targeting CTLA-4, PD-1, and IDO [
89
]. Another study by Qin et al. sought a novel approach
to depleting MDSCs. They used a peptide phage-display library to identify peptide ligands
Cancers 2021,13, 6293 9 of 14
capable of binding to MDSCs and to design a peptibody, an MDSC-specific peptide bound
to mouse IgG2b. Treatment with the peptibody caused anti-tumor effects in murine models,
and effectively depleted both granulocytic and monocytic MDSCs by recognizing S100
family proteins on the surface of MDSCS [90].
Other chemokine receptors involved in the recruitment of MDSCs to the TME include
CCR2, CCR5, CCR1, and CXCR5 [
91
]. CCR2 blockade to prevent the recruitment of TAMs
to the TME has been explored clinically [
92
]. However, it was found that CCR2 inhibitor
treatment can cause a compensatory increase in CXCR2+ neutrophils, leading to treatment
failure [
93
]. Investigating this effect further in a mouse model of pancreatic ductal adeno-
carcinoma (PDAC), Nywening et al. found that combining CCR2 inhibition with CXCR2
inhibition led to a reduction in tumor growth and an increase in tumor-infiltrating lympho-
cytes [
93
]. Single-agent treatment strategies to block the recruitment of immunosuppressive
myeloid cells to the TME have failed to find success due to compensatory pathways of
myeloid cell recruitment. However, combining CXCR2 inhibition with other strategies to
block MDSC recruitment as well as with immunotherapies may prove more successful.
9. Conclusions and Future Directions
The development of immune checkpoint inhibitors and other immunotherapies rep-
resents a major advancement in cancer research that has greatly benefited certain patient
populations. Nevertheless, many patients either do not respond to immunotherapy or de-
velop resistance after an initially promising response. MDSCs are associated with adverse
patient outcomes such as reduced overall survival and poor response to therapy, including
immunotherapy [
8
,
10
,
11
]. Targeting MDSC recruitment to the TME by blocking CXCR2 is
an emerging strategy to enhance the action of existing and novel immunotherapies.
In this review, we presented several promising pre-clinical studies that show benefit
of combining CXCR2 antagonists with immunotherapy. Much of the current literature is
focused on immune checkpoint inhibitors while data concerning CXCR2 antagonism with
immunotherapies other than checkpoint blockade are limited and necessitates further study.
As CXCR2 antagonists are developed clinically, a challenge will be to determine which
patients will benefit from a combination of immune checkpoint inhibitors and CXCR2
inhibition. Due to the associations between high MDSC infiltrates and therapy resistance
across cancer types [
7
], tumors with high levels of MDSCs or patients who have developed
resistance to prior lines of therapy may benefit from treatment with a CXCR2 antagonist.
However, inconsistencies in MDSC nomenclature in pre-clinical studies remain an obstacle
to identifying markers of response that translate clinically. Although, the recent identifica-
tion of CD14 as a marker of to distinguish G-MDSCs from neutrophils in tumor-bearing
mice [
20
] is a promising step toward overcoming this obstacle. Furthermore, given the
role of CXCR2 in maintaining the metastatic niche, CXCR2 antagonists may be particu-
larly useful in patients with late-stage or metastatic disease. However, as immunotherapy
moves toward approval for earlier-stage cancers, the potential benefit of adding a CXCR2
antagonist to improve responses warrants investigation.
Pre-clinical studies targeting other signaling axes involved in MDSC recruitment
such as CSF1R and CCR2 showed a benefit of adding CXCR2 inhibition to further deplete
MDSC populations and relieve immunosuppression [
88
93
]. Targeting multiple axes of
MDSC recruitment in conjunction with immunotherapy may provide a durable anti-tumor
response, but toxicities of such triple combinations will need to be carefully considered
before advancing this strategy clinically. Early clinical studies with CXCR2 antagonists
demonstrated safety and tolerability but failed to meet efficacy endpoints when combined
with chemotherapy [
71
]. Furthermore, blocking CXCR2 may have deleterious effects on
tumor-associated neutrophils and the effects of such therapies in relation to the relative
amount of anti-tumor N1 to pro-tumor N2 TANs in the TME necessitates further study.
Overall, targeting MDSC recruitment by blocking CXCR2 is an emerging strategy with
the potential to synergize with existing and novel immunotherapies to improve patient
responses and counteract immunosuppressive resistance mechanisms.
Cancers 2021,13, 6293 10 of 14
Author Contributions:
Conceptualization, K.B. and A.R.; investigation, K.B. and A.R.; resources,
A.R.; writing—original draft preparation, K.B.; writing—review and editing, K.B. and A.R.; visualiza-
tion, K.B.; supervision, A.R.; project administration, A.R.; funding acquisition, A.R. All authors have
read and agreed to the published version of the manuscript.
Funding:
This research was funded by the following grants: R01 CA116021(AR), R01 CA243326(AR),
VA SRCS Award IK6BX005225 (AR), VA MERIT Award 101BX002301 (AR) and P30 CA068485.
Conflicts of Interest: The authors declare no conflict of interest.
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