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The Immune Microenvironment and Cancer

Metastasis

Asmaa El-Kenawi,1,3 Kay Hänggi,1,3 and Brian Ruffell1,2

1
Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA
2
Department of Breast Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa,
Florida 33612, USA
Correspondence: Brian.Ruffell@moffitt.org

The dynamic interplay between neoplastic cells and the immune microenvironment regu-
lates every step of the metastatic process. Immune cells contribute to invasion by secreting a
cornucopia of inflammatory factors that promote epithelial-to-mesenchymal transition and
remodeling of the stroma. Cancer cells then intravasate to the circulatory system assisted by
macrophages and use several pathways to avoid recognition by cytotoxtic lymphocytes and
phagocytes. Circulating tumor cells that manage to adhere to the vasculature and encounter
premetastic niches are able to use the associated myeloid cells to extravasate into ectopic
organs and establish a dormant microscopic colony. If successful at avoiding repetitive
immune attack, dormant cells can subsequently grow into overt, clinically detectable meta-
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static lesions, which ultimately account to most cancer-related deaths. Understanding how
disseminated tumor cells evade and corrupt the immune system during the final stages of
metastasis will be pivotal in developing new therapeutic modalities that combat metastasis.

M etastasis is a multistep process character-

ized by the spread of malignant cells to
distant organs. This is evolutionary driven by
genetic and/or epigenetic alteration within can-
cer cells but is also dependent on an intricate
interaction with stromal cells at a local and sys-
temic level (Fig. 1). Tumor cells must overcome
several hurdles to establish macroscopic metas-
tasis, collectively referred to as the invasion–
metastatic cascade (Valastyan and Weinberg
2011). During this process, carcinoma cells
deviate from their primary growth site (local
invasion and intravasation), disseminate sys-
temically via circulation through the lymphatic
or vascular system (survival, arrest at distant
site, extravasation), and survive and adjust to a
new microenvironment (colonization and out-
growth) (Lambert et al. 2017). For cancer cells to
migrate through tissue, they acquire several abil-
ities that act in concert to promote invasion,
including cytoskeletal reorganization, secretion
of proteases, and altered adhesion receptor-
ligand interactions (Kessenbrock et al. 2010;
Quail and Joyce 2013). In addition, cancer
cells can undergo a reversible program termed
epithelial to mesenchymal transition (EMT)
through which loss of epithelial polarization
and intercellular adhesion allows for motility

3
These authors contributed equally to this work.
Editors: Jeffrey W. Pollard and Yibin Kang
Additional Perspectives on Metastasis: Mechanism to Therapy available at www.perspectivesinmedicine.org
Copyright © 2020 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a037424
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A. El-Kenawi et al.

(1) (2) (3) (4)

Angiogenesis

ROS
Mechanisms

Extracellular modelling
Oxygen
EMT

T cell Monocyte Macrophage Neutrophil DC ECM

Figure 1. Establishment of the tumor immune microenvironment: Environmental insults or spontaneous genetic
alterations in epithelial cells can lead to immune surveillance (1) or the growth of premalignant cells that evade
clearance by innate and adaptive immune cells (2). In addition to driving cell proliferation, certain oncogenic
alterations are associated with the release of cytokines that recruit additional immune cells to aid neoplastic
progression by providing mitogenic factors or producing reactive oxygen species that result in the accumulation
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of additional genetic mutations (3). Uncontrolled cellular growth at this stage causes environmental changes such
as reduced oxygen levels (hypoxia), extracellular matrix (ECM) turnover, and stromal disruption (4). These
signals of tissue damage result in a pathological healing response that includes the creation of a disordered and
permeable vascular network (angiogenic switch), as well as morphological and transcriptional changes in
epithelial cells that reflect a mesenchymal phenotype (EMT). Malignant cells are thus able to migrate toward
and intravasate into the vascular lumen, becoming circulating tumor cells.

and invasiveness (Thiery et al. 2009). Neoplastic
cells leaving the primary tumor and intravasat-
ing into circulation must then survive severe
physical shear stress, attack by the immune sys-
tem, and oxidative stress (Labelle et al. 2011; Le
Gal et al. 2015). Once cells arrest at a distant site
or are physically trapped in minute capillaries,
they can proliferate within the intravascular
space or extravasate by modifying the endothe-
lium (Al-Mehdi et al. 2000; Deneve et al. 2013;
Strilic and Offermanns 2017). Only a small frac-
tion of cells that disseminate from the primary
tumor will manage to invade and adapt to their
new surrounding (Nagrath et al. 2007). Thus,
the ability of neoplastic cells to co-opt immune
processes to aid in these steps and evade im-
mune recognition are necessary for successful
metastasis (Sosa et al. 2014; Massagué and Obe-
nauf 2016).
ESTABLISHMENT OF THE TUMOR IMMUNE
MICROENVIRONMENT
The tumor immune microenvironment (TIME)
promotes every aspect of carcinogenesis, includ-
ing initiation, survival, growth, metastasis, and
immune evasion. Depending on the tissue of
origin, the TIME shows a unique immune rep-
ertoire, with different proportions and function-
al states of lymphocytes, granulocytes, mono-
cytes/macrophages, and dendritic cells (DCs)
(Gentles et al. 2015). Although several of these
immune populations have the potential to erad-
icate malignant cells, numerous factors in the
tumor act to blunt this activity or redirect the
cells toward promoting tumorigenesis. In addi-
tion to relative proportions, the locations of
immune cells are associated with disease pro-
gression. For example, sites of focal myoepithe-

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Immune Microenvironment and Cancer Metastasis
lial cell layer dysregulation in ductal carcinoma
in situ (DCIS) display an enrichment of leuko-
cytes, suggesting a role in driving or sustaining
local invasion (Gil Del Alcazar et al. 2017),
whereas in late stage disease the exclusion of T
lymphocytes from tumor beds promotes resis-
tance to immune checkpoint blockade (Jayapra-
kash et al. 2018; Jerby-Arnon et al. 2018). The
degree to which parallel programs are used to
establish the metastatic immune microenviron-
ment (MIME) are largely unknown, with the
exception of myeloid cell recruitment to estab-
lish the premetastatic niche (Liu and Cao 2016).
Tumor Intrinsic Signaling
In addition to the type of cancer, immune com-
position correlates with the underlying genetic
alterations driving carcinogenesis (Rooney et al.
2015), as oncogenic signals in transformed cells
are associated with the release of chemokines
that attract immune cells to the tumor (Wellen-
stein and de Visser 2018). As one of the most
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frequently mutated genes in cancer, loss of
Trp53 activates the NF-κB pathway, stimulates
cytokines release from cancer cells, which
through paracrine interactions modify the im-
mune landscape of cancer (Meylan et al. 2009;
Kastenhuber and Lowe 2017). Similarly, the ac-
tivation of the transcription factor MYC endows
cancer cells with the ability to overproduce po-
tent proinflammatory cytokines that facilitate
tumor angiogenesis and recruitment of protu-
moral mast cells, macrophages, and neutrophils
(Soucek et al. 2007), whereas activation of the
oncogenic EGFR family of receptor tyrosine
kinases results in secretion of CSF-1, a chemo-
tactic and survival factor for macrophages.
Interestingly, oncogenic Kras G12D drives unique
programs in different cancer types, although
each cumulates in the recruitment of an im-
munosuppressive myeloid population. This in-
cludes expression of GM-CSF and CXCL3 in
pancreatic cancer and colon carcinoma, respec-
tively (Pylayeva-Gupta et al. 2012; Liao et al.
2019), as well as CCL9 expression in lung cancer
in the context of Myc activation (Kortlever et al.
2017). Oncogenic Kras and Myc also cooperate
to induce interleukin (IL)-23-dependent exclu-
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sion of lymphocytes (Kortlever et al. 2017).
Collectively, these data establish an important
role for tumor genotype in driving the immune
repertoire in cancer.
There are also several studies showing that
cells undergoing EMT modify the TIME through
chemokine secretion (Dongre and Weinberg
2019). The EMT master regulator SNAIL pro-
motes expression of CCL2 and CCL5, leading
to macrophage recruitment (Hsu et al. 2014),
and expression of CXCR2 ligands leading to re-
cruitment of suppressive myeloid cells (Taki
et al. 2018). Other mediators of epithelial mes-
enchymal transition, such as SRC-1, promote
macrophage recruitment via expression of CSF-
1 (Qin et al. 2009; Wang et al. 2009), and mesen-
chymal tumors display prominent macrophage
infiltration (Dongre et al. 2017). The ability of
EMT to promote an immunosuppressive envi-
ronment is likely further augmented by high pro-
duction of transforming growth factor (TGF)-β,
which can lead to the exclusion of lymphocytes
from tumor beds (Mariathasan et al. 2018; Taur-
iello et al. 2018) and regulate the activation state
of most immune cells. This has been shown in
one study with overexpression of SNAIL, which
leads to production of TGF-β and thrombospon-
din-1, and increased conversion of regulatory T
cells (Tregs) (Kudo-Saito et al. 2009). Given the
critical role of EMT in the metastatic process it
will be important to determine if these pathways
are also involved in establishing the MIME.
Homeostatic Imbalance
Solid tumors show large regions with low oxy-
gen levels (hypoxia) and nutrient insufficiency
(Gatenby and Gillies 2004). Hypoxia has the
ability to modulate immune functions directly
by activating HIF-1α-dependent transcriptional
changes within the immune cells, or indirectly
by rewiring tumor cell secreted metabolites and
cytokine repertoire (Cairns et al. 2007). For
example, hypoxia was shown to trigger HIF-
1α-dependent immunosuppressive activity in
macrophages (Doedens et al. 2010). Through
indirect effects on the tumor and the stroma,
hypoxia also causes the overproduction of
monocyte recruitment factors including CCL2,
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A. El-Kenawi et al.
CCL5, CXC-chemokine ligand 12 (CXCL12),
colony-stimulating factor (CSF-1), and vascular
endothelial growth factor (VEGF) (Murdoch
et al. 2004). As an indirect consequence of hyp-
oxia, tumor cells up-regulate glycolysis and se-
crete lactic acid, which induces phenotypic
changes and immunosuppressive function in
macrophages (Colegio et al. 2014). Lactate-acti-
vated macrophages in turn enhance the glyco-
lytic phenotype of breast cancer cells through the
release of extracellular vesicles containing a HIF-
1α-stabilizing long noncoding RNA (Chen et al.
2019). The acidic microenvironment of tumors
also directly regulates macrophage phenotype,
as seen following the genetic ablation of the
macrophage pH sensor, Gpr132, or the buffer-
ing of tumor secreted acids, which reduces the
spontaneous lung metastasis of breast cancer
cells and prostate cancer invasiveness, respec-
tively (Chen et al. 2017a; El-Kenawi et al.
2019). Finally, areas of hypoxia frequently coin-
cide with regions of cell death, leading to recog-
nition of apoptotic cells by phagocytes and/or
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the release of damage-associated molecular pat-
terns (DAMPs) during secondary necrosis.
Phosphatidylserine recognition receptors thus
promote myeloid-dependent immune suppres-
sion in the TIME (Cook et al. 2013; Crittenden
et al. 2016; Ubil et al. 2018); whereas several
DAMPs have been shown to activate DCs and
elicit a cytotoxic T-cell response (Kroemer et al.
2013).
Immune-Stroma Crosstalk
In addition to regulating the immune compart-
ment directly, tumor cells drive phenotypic
changes in the nonimmune stromal cells, in-
cluding fibroblasts, endothelial cells, and peri-
cytes. This “reactive” stroma possesses a unique
gene/protein expression profile that differs from
the signature of the corresponding normal tissue
(Finak et al. 2008; Nonn et al. 2009) and is cre-
ated, in part, by the influence of inflammatory
mediators and cytokines. For example, TGF-β
cooperates with SDF-1 (CXCL12) to generate
myofibroblasts with enhanced tumor-promot-
ing capability through autocrine signaling loops
(Kojima et al. 2010). Cancer-associated fibro-
4 Cite this article as Cold Spring Harb Perspect Med 2020;10:a037424
blasts can suppress a T-cell response through a
myriad of pathways, including direct suppres-
sion via PD-L2 and FAS ligand expression (La-
kins et al. 2018), expression of cytokines (Kato
et al. 2018), and recruitment of immuno-
suppressive myeloid cells (Kumar et al. 2017).
Cancer cells can even create gap junctions with
astrocytes to transfer the second messenger
cGAMP to astrocytes, activating the STING
pathway and production of type I interferons
(Chen et al. 2016). It should also be noted that
changes in the physical properties of the stroma
further modulate the TIME (DeNardo and Ruf-
fell 2019). For example, higher levels of collagen
(Wesley et al. 1998; Stahl et al. 2013; Pickup et al.
2014) and collagen cross-linking (Van Goethem
et al. 2010; McWhorter et al. 2015) enhance the
protumoral phenotype of macrophages, and in-
hibiting the hyperactivation of focal adhesion
kinase (FAK) is sufficient to alter macrophage
polarization and increase response to immune
checkpoint blockade (Jiang et al. 2016).
There is also an elaborate interplay between
immune cells in the tumor that controls the phe-
notype and functional role of the cells. Most
well established is the ability of macrophages,
monocytes, neutrophils, and other myeloid popu-
lations to suppress the cytotoxic function of lym-
phocytes, through mechanisms that have been
reviewed elsewhere (Veglia et al. 2018; DeNardo
and Ruffell 2019). As will be discussed, myeloid
cells are a critical component of the immuno-
suppressive TIME and MIME, and depleting
these cells can reduce metastasis by unleashing
T and natural killer (NK) cell cytotoxicity. Sim-
ilarly, Tregs promote pulmonary metastasis by
blocking NK cell function (Olkhanud et al.
2009), with Treg conversion occurring through
the activity of Bregs (Olkhanud et al. 2011). T and
B lymphocytes can also promote the protumori-
genic properties of macrophages (Gunderson
and Coussens 2013), including IL-4-producing
CD4+ T cells enhancing the ability of macro-
phages to foster invasion (DeNardo et al. 2009).
INVASION AND INTRAVASATION
Cancer cells must acquire phenotypic changes
that endow them with ability to invade sur-
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Immune Microenvironment and Cancer Metastasis
rounding stroma as a precursor to intravasation.
These invasive characteristics include alter-
ations in expression of adhesion molecules and
expression of proteases to degrade the extracel-
lular matrix (ECM). Each of these characteristics
is fuelled by the presence of immune cells and
can potentially cross-regulate each other. For
example, EMT leads to the recruitment of mac-
rophages, which can secrete and activate TGF-β,
further supporting the induction of EMT (Don-
gre and Weinberg 2019). Similar feedback loops
are required for intravasation, with tumor cells
stimulating the chemotactic and angiogenic
properties of macrophages (Lewis et al. 2016).
Interestingly, recent studies have shown that
cells egressing the primary site early during can-
cer progression are more metastasis-efficient
than cells leaving the tumor at later stages (Hü-
semann et al. 2008; Ghajar and Bissell 2016;
Harper et al. 2016; Hosseini et al. 2016). The
metastatic competency of early disseminated
cells—which would harbor fewer mutations—
reiterates that microenvironmental factors con-
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tributes to the acquisition of metastatic traits
(Hendry et al. 2017; Linde et al. 2018). In sup-
port of this, although the molecular profiles of
invasive breast cancer and preinvasive was in-
distinguishable, aggressive lesions displayed
high infiltration of macrophages and Tregs
(Abba et al. 2015; Nelson et al. 2018).
Epithelial-to-Mesenchymal Transition
An established TIME provides several cytokines
and chemokines with the potential to activate
latent EMT programming in epithelial cells,
causing decreased E-cadherin expression, loss
of cell–cell junction and, morphological chang-
es that enable cells to invade and migrate to dis-
tant sites (Dongre and Weinberg 2019). This can
be mediated through cooperation with the TGF-
β signaling pathway, one of the primary induces
of EMT (Lu et al. 2014; Su et al. 2014; Chockley
and Keshamouni 2016), although independent
mechanisms have also been described. For ex-
ample, in a model of gastric cancer, macrophage
production of CXCL1 and CXCL5 increase Snail
transcription through activation of a CXCR2/
STAT3 feed-forward loop (Zhou et al. 2019),
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whereas in a model of Her2+ breast cancer
Tie2+ macrophages initiate EMT through ex-
pression of Wnt (Linde et al. 2018). This asso-
ciation in breast cancer drives dissemination in
the absence of a palpable lesion (Linde et al.
2018), and thus may also explain the impact of
macrophage ablation on the invasive phenotype
in a model of Trp53 null breast cancer (Carron
et al. 2017). Intriguingly, macrophage expres-
sion of IL-35 at the site of metastasis has recently
been shown to promote mesenchymal-to-epi-
thelial transition (Lee et al. 2018), highlighting
the critical role of macrophages at multiple stag-
es of the metastatic process.
Immature monocytes and neutrophils have
also been shown to contribute to EMT through
the production of TGF-β, epidermal growth
factor (EGF), and hepatocyte growth factor
(HGF), and these cells are found around the
invasive edge of tumors in which markers of
EMT are most prevalent (Toh et al. 2011; San-
galetti et al. 2016; Ouzounova et al. 2017; Wang
et al. 2019), with neutrophil levels at the inva-
sive margin of gastric cancer being an indepen-
dent, negative predictor of disease-free survival
(Li et al. 2019). Neutrophils have also been
shown to contribute to EMT by creating abnor-
mal vasculature in lung tumors, resulting in
hypoxia and induction of a Snail-dependent
EMT program (Faget et al. 2017). Given an
analogous role for macrophages in breast can-
cer (Stockmann et al. 2008), it may be that
macrophages promote EMT through the same
mechanism.
Although it has not been extensively evalu-
ated, there are also a few reports suggesting that
T cells can activate EMT. In vitro, coculturing
premalignant cells with CD4+ T cells decreased
E-cadherin expression and elevated expression
of mesenchymal proteins (Goebel et al. 2015;
Chen et al. 2017b). Whether this is mediated
by TGF-β production by Tregs is not clear (Li
et al. 2007; Worthington et al. 2012). One study
also observed an in vivo role for CD8+ T cells
involving selection of Her2/neu escape variants
(Santisteban et al. 2009). However, this may be
an artifact of this particular model system, and a
role for T cells in vessel normalization (Motz
et al. 2014; Schmittnaegel et al. 2017; Tian
5
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A. El-Kenawi et al.
et al. 2017) suggests these cells could actually
reduce hypoxia and EMT in other settings.
Extracellular Matrix Remodeling
The ECM is a dynamic, acellular, three-dimen-
sional structure that serves as scaffold, on-de-
mand reservoir for growth factors, and ligand
for cellular adhesion. The ECM undergoes a
continuous process of remodeling that is tightly
regulated by the MMP and cathepsin family of
proteases (Bonnans et al. 2014). Not surpris-
ingly, ECM remodeling is highly abnormal
in tumors, with increased deposition of key
components such as collagen and fibronectin,
increased degradation and turnover, and an ab-
normal structure marked by higher density and
tensile force (Northey et al. 2017). Navigating
the ECM is thus critical for cancer cells to invade
tissue and gain access to the vasculature.
Studies documenting a role for immune cells
in ECM deposition are limited, but production
of SPARC (secreted protein, acidic rich in cys-
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teine) by macrophages leads to increases in
collagen and fibronectin, along with higher lev-
els of metastasis (Sangaletti et al. 2008). Inflam-
matory monocytes have also been shown to elic-
it FXIIIA-mediated fibrin cross-linking, which
provides a scaffold for local tumor cell invasion
(Porrello et al. 2018). Conversely, production of
interferon (IFN)-γ by NK cells restricts metas-
tasis by inducing expression of fibronectin
(Glasner et al. 2018), highlighting the complex
association of ECM location and structure with
the invasive process. A number of stromal pro-
teases are also known to promote local tumor
invasion, including urokinase/plasminogen ac-
tivator (uPA), MMP-9 and cathepsin B, S, or Z
(Almholt et al. 2005; Vasiljeva et al. 2006; Yang
et al. 2008; Gocheva et al. 2010; Yan et al. 2010;
Bekes et al. 2011; Akkari et al. 2014). Most
of these proteases are expressed primarily by
tumor macrophages, with the exception of
MMP-9, which is also expressed by neutrophils
and mast cells (Coussens et al. 2000; Bekes et al.
2011). However, it is currently unclear whether
these proteases act by clearing out the ECM to
permit invasion, release factors that promote an
invasive phenotype (e.g., active TGF-β), alter the
6 Cite this article as Cold Spring Harb Perspect Med 2020;10:a037424
structure of the ECM to facilitate the creation of
“tracks,” or act through some combination
thereof (Condeelis and Segall 2003).
Intravasation
Angiogenesis is a hallmark of cancer, and angio-
genic factors such as VEGF, fibroblast growth
factor (FGF), and placental-derived growth fac-
tor (PlGF) are produced by immune cells in the
tumor, especially macrophages (Rivera and
Bergers 2015), which are critical for the angio-
genic switch during tumor development (Lin
et al. 2006). Macrophage production of these
factors does not necessarily regulate the extent
of angiogenesis in late stage tumors, as VEGF
overexpression can bypass a requirement for
macrophages (Lin et al. 2007). However, macro-
phages retain their importance as regulators of
vascular structure and permeability (Stockmann
et al. 2008). Thus ablating macrophages produc-
tion of VEGF increases pericyte coverage, im-
proves tissue perfusion, and increases tumor
growth (Stockmann et al. 2008), while simulta-
neously increasing susceptibility to chemother-
apy (Stockmann et al. 2008; Hughes et al. 2015)
and reducing intravsation and metastasis (Har-
ney et al. 2015). This phenotype is driven largely
by a population of Tie2+CXCR4+ macrophages
that reside in the perivascular space around ves-
sels (De Palma et al. 2005; Welford et al. 2011),
allowing for local production of VEGF to in-
crease vessel permeability and ease transendo-
thelial migration (Harney et al. 2015). Targeting
these cells by blocking the ligand for Tie2, an-
giopoietin (Ang)-2, thus also results in reduced
metastasis (Mazzieri et al. 2011). Although not
necessarily related to the metastatic cascade, it is
worth noting that vessel normalization pro-
motes T-cell infiltration, which then maintains
vessel normalization by producing IFN-γ (Motz
et al. 2014; Schmittnaegel et al. 2017; Tian et al.
2017).
Macrophages are also responsible for re-
cruiting tumor cells to these sites of vascular
permeability through a well-described paracrine
loop involving epidermal growth factor (EGF).
As mentioned, tumor cells are an important
source of CSF-1, and this induces the produc-
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Immune Microenvironment and Cancer Metastasis
tion of EGF in macrophages, resulting in tumor
cell chemotaxis toward the vasculature (Wyck-
off et al. 2004, 2007; Wang et al. 2009; Ishihara
et al. 2013). This process is not mediated by
Tie2+ perivascular macrophages, but rather the
recently recruited population of monocyte-
derived macrophages that forms the dominant
population within tumors (Arwert et al.
2018). After entering the tumor parenchyma,
these macrophages up-regulate expression of
CXCR4 and are slowly recruited back to the
vasculature via CXCL12-expressing fibroblasts,
creating an EGF chemotactic gradient and path-
way of altered ECM that directs cancer cell mi-
gration to the vasculature (Arwert et al. 2018).
Finally, endothelial cell interactions promote
differentiation into the Tie2+CXCR4+ perivas-
cular macrophage population that facilitates
transendothelial migration. Thus, interfering
with monocyte recruitment (CCR2-CCL2), sur-
vival and differentiation (CSF1R-CSF1), migra-
tion to the vasculature (CXCR4-CXCL12), or
maturation to perivascular cells (Tie2-Ang2)
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functions to severely limit the ability of tumor
cells to intravasate into the blood stream (Qian
and Pollard 2010; Kitamura et al. 2015). As with
vascular normalization, the ability of macro-
phages to promote tumor cell chemotaxis is
controlled by infiltrating T cells, with IL-4-ex-
pressing CD4+ T cells augmenting EGF expres-
sion by macrophages (DeNardo et al. 2009).
SURVIVAL AND EXTRAVASATION
Most primary tumors release millions of cells
into the blood stream, but only a small number
of metastatic lesions usually develop, indicating
the inefficiency of tumor cell dissemination
(Nagrath et al. 2007). In particular, circulating
tumor cells (CTCs) have to resist physical shear
stress caused by blood flow, death by anoikis,
and avoid recognition by cytotoxic lymphocytes
and phagocytic macrophages (Fig. 2) (Mohme
et al. 2017). With this limited capacity to survive
within the vasculature, the capacity of CTCs to
adhere to the vasculature and migrate into the
extravascular space is also central to their met-
astatic potential (Reymond et al. 2013), process-
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es that are linked to the recruitment of neutro-
phils and monocytes/macrophages.
Avoiding Cytotoxic Cells
Increased NK cell cytotoxicity or enhanced ex-
pression of NK cell activation receptors are as-
sociated with good prognosis for patients at risk
of metastatic disease (López-Soto et al. 2017).
For example, the infiltration of NK cells express-
ing high levels of the activating receptors NCR1/
NKp46 (natural cytotoxicity triggering receptor
1) and NKG2D (killer cell lectin-like receptor
K1) was positively associated with recurrence-
free survival in prostate cancer following surgi-
cal resection (Pasero et al. 2016). Several studies
have shown that NKp46 expression in particular
is critical for NK cell recognition of metastatic
cells (Halfteck et al. 2009; Lakshmikanth et al.
2009; Elboim et al. 2010; Glasner et al. 2012) and
loss of NK cells increases metastasis (Smyth
et al. 1999; Bidwell et al. 2012). Although it is
difficult to distinguish between a role for NK
cells within the primary tumor, circulation, or
metastatic sites, at least some experimental evi-
dence exists for the direct killing of CTCs (Pal-
umbo et al. 2005; Hanna et al. 2015), and poor
infiltration by NK cells in the absence of treat-
ment likely limits their role in most primary
tumors (Böttcher et al. 2018).
Not surprisingly, tumors use multiple mech-
anisms to avoid recognition by NK cells (Box 1).
First and foremost, down-regulated protein or
surface expression of NK activating ligands, es-
pecially MHC I polypeptide-related sequence A
(MICA), and MICB, can reduce NK cell recog-
nition and killing of tumor cells (Nausch and
Cerwenka 2008; Wang et al. 2014). Conversely,
tumor cells can secrete soluble versions of these
same molecules to suppress NK cell immuno-
surveillance (Schlecker et al. 2014; Zhang et al.
2015). This occurs within the primary tumor,
but is sufficient to drive a systemic reduction
in the cognate receptors on NK cells (Pasero
et al. 2016), and high levels of these soluble li-
gands in the circulation correlate with disease
progression (Paschen et al. 2009; Yamaguchi
et al. 2012). That said, a high-affinity NKG2D
ligand (MULT1) has also been shown to stimu-
7
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A. El-Kenawi et al.

Survival in the blood stream

Endothelial cell (EC) layer

Cancer cell
1
3
Apoptotic
cancer cell

4
2 Neutrophil

Platelets

Adherence extravasation
Monocyte

Macrophage

Activating
receptor
5 6 7 8
NK cell
Inhibitory
receptor

Figure 2. Immune evasion and assistance during cancer cell dissemination. During circulation within the
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intravascular space, major histocompatibility complex (MHC) I expression protects by circulating tumor cells
(CTCs) from natural killer (NK) cell recognition (1), whereas down-regulation of MHC I and up-regulation of
NK cell activating ligands can lead to cytotoxicity (2). Conversely, recognition can be antagonized via up-
regulation of NK cell inhibitory ligands (3) or physical shielding using platelet/fibrin coagulates (4). To extrav-
asate into the tissue, CTCs interact with endothelial cells via selectins, cadherins, integrins, CD44, junctional
adhesion molecules (5). Neutrophils are able to assist this process via ICAM-1 and VCAM-1 interactions, as
well as through the release of NETs that trap CTCs and hide the cells from lympohcytes (6). Recruitment of
CCR2+Ly6C+ monocytes (7) results in local production of VEGF, thereby increasing vascular permeability to
facilitate CTC extravasation (8).

late NK cell-mediated killing of tumor cells after
shedding (Deng et al. 2015), so there may be a
cost to this approach in some instances. Second,
although HLA down-regulation is a common
mechanism of evading T-cell recognition (Cam-
poli and Ferrone 2008), HLA expression is never
completely lost, likely because of the selective
pressure of NK cells. Instead, HLA loss of het-
erozygosity is commonly observed as an alter-
native to loss of neoantigen expression, allowing
tumors to limit detection by both of the cytotox-
ic lymphocyte populations simultaneously
(McGranahan et al. 2017; Rosenthal et al. 2019).
There is also a complex interaction between
tumor cells, platelets, and NK cells that regulates
cytoxicity in the blood. Tumor cells become
coated with platelets on entering the circulation,
and this can promote survival, EMT, and adhe-
sion to the endothelium (Gay and Felding-Hab-
ermann 2011; Labelle et al. 2011). This also has
the effect of physically masking CTCs from NK
cells (Camerer et al. 2004; Palumbo et al. 2005)
and/or transferring platelet-derived membrane
vesicles containing MHC I molecules that act to
“normalize” the tumor cells (Placke et al. 2012).
Additionally, platelet-derived TGF-β has been
shown to induce down-regulation of NKG2D
to prevent NK cell reactivity (Kopp et al.
2009). Cumulatively, platelets and their associ-
ated factors promote metastatic spread, a phe-
notype that is dependent on the presence of NK
cells in most models (Camerer et al. 2004; Pal-
umbo et al. 2005; Palumbo 2008; Turpin et al.
2014; Adams et al. 2015).

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Immune Microenvironment and Cancer Metastasis

BOX 1. NONCLASSICAL MHC SIGNALING

Histocompatibility antigen class I G (HLA-G) is a human leukocyte antigen that belongs to the
“nonclassical” HLA-class Ib molecules (Choo 2007). HLA-Ib molecules have minimal polymor-
phisms compared with the HLA-Ia molecules and are involved in immune modulation rather than
antigen presentation (Kievits et al. 1987; Braud et al. 1997). HLA-G has been described to contribute
to immune evasion in cancer (Lin and Yan 2015) and expression correlates with poor patient survival
in melanoma, colorectal, hepatocellular, breast, glioma, ovarian, and lung cancers (Cai et al. 2009;
de Kruijf et al. 2010; He et al. 2010; Guo et al. 2015). Moreover, soluble HLA-G is secreted by the
primary tumor were identified and negatively correlate with patient outcome (Contini et al. 2003;
Zheng et al. 2014). HLA-G can bind to a variety of receptors, such as CD8, leukocyte immunoglob-
ulin-like receptor subfamily B member 1 (LIR-1), and killer cell immunoglobulin-like receptor (KIR),
all of which protect cancer cells from CD8 T cell- or NK cell-induced killing (Wiendl et al. 2002;
Kochan et al. 2013; Loumagne et al. 2014; Lin and Yan 2015). HLA-G polymorphisms also impact
graft-versus-tumor responses in renal cell carcinoma (Crocchiolo et al. 2018) and correlate with
outcome in epithelial ovarian carcinoma (Schwich et al. 2019).

Avoiding Phagocytosis metastasis and decreased survival (Baccelli

et al. 2013, 2014). Taken together, the evidence
CD47 is a surface protein belonging to the im-
favors CD47 expression reducing clearance by
munoglobulin superfamily that regulates a
monocytes/macrophages. The question remains
broad range of cellular functions, including
whether this clearance is relevant within the in-
adhesion, migration, proliferation, apoptosis
www.perspectivesinmedicine.org

travascular or extravascular space. It seems un-

and—most relevant for metastasis—recogni-
likely that monocytes and CTCs are interacting
tion by phagocytes via signal regulatory protein
while they are both in circulation. However,
α (SIRPα) (Reinhold et al. 1995; Jiang et al.
nonclassical Ly6C− monocytes actively patrol
1999). SIRPα is expressed on monocytes, mac-
the endothelial lumen (Auffray et al. 2007; Car-
rophages, and CD11b+ classical dendritic cells
lin et al. 2013) and rapidly take up cellular debris
(cDCs), and on binding to CD47 the phagocyt-
(Headley et al. 2016), which induces chemokine
ic activity of these cells is blocked, thereby act-
expression and recruitment of NK cells to limit
ing as a “don’t eat me” signal (Jaiswal et al.
metastasis (Hanna et al. 2015). Whether these
2009). CD47 is ubiquitously expressed on
patrolling monocytes also phagocytose live cells
mouse and human myeloid leukemias, thereby
is unclear, and it may be that phagocytosis in the
allowing them to evade clearance and populate
extravascular space or tissue parenchyma plays a
organs with an abundance of macrophages
more critical role in restricting metastasis.
(Jaiswal et al. 2009) and hinting that the same
process may allow for CTCs to colonize ectopic
organs.
Adhesion to the Endothelium
Certainly, CD47 is overexpressed in many
solid tumors (Liu et al. 2017), and it can protect Circulating neutrophils correlate with poor
cancer stem cells from elimination during con- prognosis (Teramukai et al. 2009; Lee et al.
ventional antitumor therapies, which in turn 2012; Gondo et al. 2013), and although this
increases the probability of recurrence (Solta- may partially reflect altered hematopoiesis and
nian and Matin 2011). Gene expression profil- the establishment of an immunosuppressive mi-
ing of primary tumors and CTCs from patients croenvironment (Coffelt et al. 2015), it has also
with colorectal cancers also found pronounced become increasingly clear that circulating neu-
expression of CD47 (Steinert et al. 2014), where- trophils promote the conversion of CTCs to
as the presence of CD47+MET+CTCs in breast disseminated tumor cells (DTCs) through two
cancer patients was associated with increased distinct mechanisms. The first involves binding

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A. El-Kenawi et al.

between integrins expressed by neutrophils (i.e.,
CD11b/CD18, VLA-4) and immunoglobulin
superfamily ligands expressed by endothelial
cells and CTCs (ICAM-1, VCAM-1). This al-
lows neutrophils to form a cellular bridge for
CTCs to adhere to the endothelium (Box 2)
(Huh et al. 2010; Spicer et al. 2012). These inter-
actions also induce “outside-in” signaling that
promotes the proliferative capacity of CTCs, en-
hancing their metastatic potential (Szczerba
et al. 2019). As the majority of CTCs are associ-
ated with neutrophils—at least in breast cancer
patients—this appears to be an important mech-
anism underlying metastatic spread (Szczerba
et al. 2019).
The other major mechanism by which neu-
trophils promote metastasis is through the re-
lease of neutrophil extracellular traps (NETs)
containing their nuclear DNA (Park et al.
2016). Originally described to trap CTCs during
injury or infection (Tohme et al. 2016), it has also
been shown that release of NETs can be induced
by the presence of CTCs in the lungs, leading to
www.perspectivesinmedicine.org
in circulation (Szczerba et al. 2019) and the abil-
ity of tumor cells to induce the release of
NETs109, it will be interesting to determine if
this alters the dynamics of CTC retention and/
or allows CTCs to create their own protective
shell.
Extravasation
Ly6C+CCR2HI monocytes are recruited to the
site of CTC arrest via a classical multistep ad-
hesion cascade involving selectins, chemokines,
and integrin ligands (Qian et al. 2011; Ferjančič
et al. 2013; Häuselmann et al. 2016). In addition
to CCL2 emanating from the tissue, cancer cell
production of CCL2 is necessary for this pro-
cess (Qian et al. 2011; Häuselmann et al. 2016),
suggesting that it initiates the inflammatory
cascade. Reminiscent of the role of macrophag-
es in tumor cell intravasation, monocytes re-
cruited to the endothelial lumen via CCL2
secrete VEGF and increase endothelial perme-
ability, thereby enhancing transmigration of tu-

an increase in micrometastasis (Cools-Lartigue
et al. 2013; Najmeh et al. 2017). Beyond simply
sequestering CTCs, NETs inhibit NK cell-medi-
ated cytotoxicity, and the release of factors such
as IL-1B, MMP-9, and HMGB1 promotes ex-
travasation (Spiegel et al. 2016; Tohme et al.
2016). Importantly, the formation of NETs in
postoperative patients was linked to a reduction
in survival, highlighting the potential clinical rel-
evance of this mechanism (Tohme et al. 2016).
Given the prevalence of CTC-neutrophil clusters
mor cells (Qian et al. 2011). Interfering with the
CCR2/CCL2 chemokine axis thereby reduces
liver and lung metastasis in multiple murine
model systems (Qian et al. 2011; Sanford et al.
2013), provided that the mice are left on treat-
ment for the duration of the study (Bonapace
et al. 2014). Platelet-bound CTCs can also re-
cruit monocytes to promote metastasis, but the
degree to which this process involves CCL2
and/or VEGF is unknown (Gil-Bernabe et al.
2012).

BOX 2. TUMOR–ENDOTHELIAL CELL INTERACTIONS

CTCs becoming trapped in the capillaries is thought to be one of the major mechanisms of arrest in the
circulation, but the process of adhesion to the endothelial layer and migration into the tissue is an
active process (Chambers et al. 2002; Wirz et al. 2008; Strilic and Offermanns 2017). The vascular
endothelium differs structurally depending on the organ, and as a result, leukocyte extravasation in
lung and liver occurs in the microvasculature, whereas it occurs in the postcapillary venules in the
skin, muscle, and mesentery (Aird 2007; Strell and Entschladen 2008). However, although the pro-
cesses of adhesion and transmigration (diapedesis) are at least partially shared between leukocytes
and tumor cells (Miles et al. 2008), the molecules described for tumor cell transmigration vary and are
often tumor-specific (Bendas and Borsig 2012; Strilic and Offermanns 2017). However, it is still not
entirely clear the degree to which all of these molecules are involved in tumor cell adhesion/trans-
migration in vivo, or whether different tumor subclones may use unique strategies to colonize different
tissues (Caswell and Swanton 2017).

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Immune Microenvironment and Cancer Metastasis
ECTOPIC GROWTH
Outgrowth of metastatic colonies represents the
final stage of disease and is responsible for the
majority of cancer-related deaths, and unfortu-
nately, there is evidence that most patients have
DTCs at the time of diagnosis (Friberg and Ny-
strom 2015; Massagué and Obenauf 2016).
These DTCs are largely in a dormant state and
thus resistant to conventional cytotoxic chemo-
therapies, resulting in metastatic recurrence for
many patients long after the primary tumor has
been removed. Addressing the issue of DTCs, as
well as the treatment of overt metastasis, are
therefore the two most critical areas of cancer
research (Sosa et al. 2014; Massagué and Obe-
nauf 2016). Thankfully, it is becoming clear that
modulating the immune response has the
potential to address both of these issues, with
the approval of immune checkpoint blockade
agents for metastatic disease being the most sig-
nificant advancement.
www.perspectivesinmedicine.org
Formation of the Premetastatic Niche
The premetastatic niche was originally de-
scribed as VEGFR1-expressing myeloid cells ac-
cumulating at sites of distant metastasis before
the arrival of tumor cells (Kaplan et al. 2005),
and is usually defined by the recruitment of
macrophages and neutrophils (Fig. 3) (Liu and
Cao 2016). The formation of the niche is driven
by a range of tumor and stroma-derived soluble
factors (e.g., G-CSF, VEGF, CCL2, TNF-α, TGF-
β, S100A8/A9) in addition to the release of
tumor-derived extracellular vesicles (usually
containing microRNAs [mRNAs]) (Liu and
Cao 2016). Regardless of the molecules identi-
fied or the mechanism proposed, each appears
to act primarily by inducing the recruitment of
myeloid cells. For example, S100A8/A9 pro-
motes the release of serum amyloid A3, which
activates an inflammatory program in macro-
phages via toll-like receptor (TLR)4 (Hiratsuka
et al. 2008). These cells then promote the ability
of DTCs to become established by generating an
immunosuppressive and/or permissive micro-
environment, as we will discuss below. It is un-
clear why so many divergent approaches are
Cite this article as Cold Spring Harb Perspect Med 2020;10:a037424
used to achieve a similar goal, but presumably
there are subtleties in the activation state of the
recruited myeloid cells, as well as alternations in
the functions of other stromal cells that play a
complementary and supportive role in estab-
lishing the niche (McAllister and Weinberg
2014; Peinado et al. 2017).
Escaping Dormancy
There is only limited evidence that immune cells
can promote the survival and growth of DTCs
(Qian and Pollard 2010), with macrophages
shown to provide survival signals via binding
to VCAM-1 (Chen et al. 2011) and neutrophils
enhancing tumorigenicity via leukotriene pro-
duction (Wculek and Malanchi 2015). However,
macrophages in primary tumors promote ther-
apeutic resistance by producing factors such as
TNF-α and IL-6 (Ruffell and Coussens 2015),
which activate signaling pathways known to
promote the proliferation of dormant cells
(Massagué and Obenauf 2016). Thus, it is likely
that these and other pathways are important at
the metastatic site, and that our limited knowl-
edge in this area reflects experimental difficulties
evaluating the early stages of colonization. This
includes the use of murine cancer cell lines that
do not display dormancy or extended periods of
latency, and evaluation of metastasis primarily
to the lung even though there is evidence of a
tissue-specific role for critical molecules such as
TGF-β (Massagué and Obenauf 2016). Indeed,
using a model of metastatic dormancy, it was
recently shown that NETs promote metastasis
via release of neutrophil elastase and MMP9,
resulting in cleavage of the ECM component
laminin (Albrengues et al. 2018). Rather than
activating myeloid cells via TLRs, as has been
described for versican in the premetastatic niche
(Kim et al. 2009), cleaved laminin triggered tu-
mor cell proliferation via integrin activation and
FAK signaling (Albrengues et al. 2018).
Other studies that have addressed these
experimental issues have noted a clear role for
lymphocytes in maintaining tumor dormancy.
CD8+ T-cell-depletion dramatically increased
the rate of metastasis in a model of spontaneous
uveal melanoma (Eyles et al. 2010) and following
11
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A. El-Kenawi et al.

Preparation of the pre-

1
metastatic niche Cancer cell

Apoptotic
cancer cell

Extracellular vesicles/
exosomes
Growth factors, cytokines
chemokines and MMPs

Neutrophil
2 Colonization

Monocyte

3 Outgrowth Macrophage

NK cell

T lymphocyte
www.perspectivesinmedicine.org

Figure 3. Establishment of the metastatic immune microenvironment: The primary tumor can actively prime
organs by forming a metastasis-permissive microenvironment before the arrival of disseminated tumor cells
(DTCs) (1). This premetastatic niche includes recruited monocytes, macrophages, and neutrophils, as well as
tumor-secreted factors such as cytokines, chemokines, growth factors, and proteases. Enhanced vascular leak-
iness, reorganization of the stroma and extracellular matrix, and the establishment of an immunosuppressive
environment are hallmarks of the metastatic microenvironment (2). These allow DTCs to evade natural killer
(NK) cell immunity and colonize the ectopic organ as single cells or micrometastatic lesions. Micrometastatic
lesions often enter a period of dormancy, as they are ill-adapted to the new microenvironment, encounter growth
suppressive factors such as TGF-β, and are subjected to NK cell-mediated immune surveillance. Outgrowth
involves tumor-intrinsic changes alongside the induction of angiogenesis and the creation of a mature immu-
nosuppressive microenvironment to evade recognition by cytotoxic lymphocytes (3).

the surgical resection of implanted fibrosarcoma
(Romero et al. 2014). Interestingly, although
CD8+ T-cell-depletion resulted in a 100% rate
of metastasis, NK cell-depletion led to a rate of
87%, and CD4+ T-cell-depletion resulted in a
rate of 23% (Romero et al. 2014). This may reflect
a complex interplay between these cell types in
maintaining dormancy, or simply the produc-
tion of a common set of cytokines such as
IFN-γ and TNF-α. Certainly, the incidence of
primary tumors is suppressed by these cytokines
(Müller-Hermelink et al. 2008), either through
cytostatic/cytotoxic effects on carcinoma cells or
via suppression of angiogenic pathways (Müller-
Hermelink et al. 2008; Andreu et al. 2010).
Critically, a functional immune system prevents
disease recurrence in humans, as seen from the
unfortunate development of metastasis follow-
ing kidney transplantations from donors with a
previous history of melanoma or lung cancer
(MacKie et al. 2003; Xiao et al. 2013).
Evading Immunity
Leaving the immunosuppressive microenviron-
ment of the primary tumor exposes metastatic

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Immune Microenvironment and Cancer Metastasis

cells to recognition by cytotoxic lymphocytes, as SUMMARY

seen from the ability of NK cells to protect
The mechanisms underlying early steps of the
against experimental and spontaneous metasta-
metastatic process have been relatively well stud-
sis but not primary tumor growth (Smyth et al.
ied compared with colonization and immune
1999, 2001; Takeda et al. 2001; Olkhanud et al.
evasion, despite early dissemination of tumor
2009; Milsom et al. 2013; Paolino et al. 2014).
cells making these later steps more clinically
Thus, it is not surprising that successful metas-
relevant. The critical role for T cell- and NK
tasis is linked to the formation of a myeloid-rich
cell-mediated surveillance in restraining the
environment (de Mingo Pulido and Ruffell
growth of metastatic lesions represents a unique
2016). What remains largely unexplored is the
therapeutic opportunity as agents that promote
degree to which immunosuppressive mecha-
the activity of these cells become available. In
nisms used by metastatic cells recapitulate those
addition to approved antagonist antibodies
found in the primary tumor, represent the
against CTLA-4 and PD-1/PD-L1, agents block-
unique biology of the ectopic organ, and/or re-
ing LAG-3, TIGIT, and TIM-3 are in early phase
flect an incipient microenvironment. For exam-
clinical trials (Anderson et al. 2016), whereas
ple, in a model of lobular breast cancer, primary
several new targets have been identified, includ-
tumors drive neutrophil expansion and an im-
ing those that unleash NK cell activity (André
munosuppressive phenotype via initiation of an
et al. 2018). Combining these agents with those
IL-1β/IL-17/G-CSF cascade, which acts to blunt
that block the inhibitory function of myeloid
CD8+ T-cell-dependent rejection of early meta-
cells, or activate their immunostimulatory po-
static lesions (Coffelt et al. 2015). Interfering
tential, have already shown potential in murine
with any component of this pathway reversed
models of primary tumors (DeNardo and Ruf-
this immune suppression, but had no impact
www.perspectivesinmedicine.org

fell 2019).
on any measured parameter within primary tu-
Beyond the treatment of overt metastatic le-
mors. This discrepancy may relate to the size of
sions, the role of lymphocytes in maintaining
the lesion, as the complexity of an advanced
dormancy suggests the possibility of developing
microenvironment would make it resistant to
immunotherapies in an adjuvant setting. Al-
perturbations in a single pathway and late stage
though long-term treatment is difficult and
metastatic lesions were not impacted by neutro-
expensive, the potential benefit of preventing
phil depletion (Coffelt et al. 2015). However, it
recurrence would be immense, and the use of a
has also been described that macrophages in pri-
minimal effective dose could improve the viabil-
mary tumors indirectly suppress a CD8+ T-cell-
ity of this approach. Alternatively, understand-
response through production of IL-10, whereas
ing how the immune system promotes escape
their ability to limit T-cell activity in metastatic
from dormancy could allow for the develop-
tumors occurs through a different mechanism of
ment of therapies targeting systemic inflam-
action (Ruffell et al. 2014), such as the produc-
mation. Recent technological developments
tion of reactive oxygen species or expression of
including CRISPR/Cas9 screens, single cell ge-
CTLA4 ligands (Kitamura et al. 2018). Con-
nomics, and mass cytometry will allow progress
versely, the clinical success of immune check-
to be made in this area, and dissecting how life
point blockade in metastatic and primary
events such as inflammatory diseases, infec-
tumors, including in relatively immune privi-
tions, and injury relate to recurrence-free sur-
leged sites, highlights the importance of tumor
vival should allow findings in murine models to
immunogenicity (Hodi et al. 2014; Topalian
be correlated with patient data.
et al. 2014; Overman et al. 2018). Thus, intrinsic,
extrinsic, and temporal factors appear to regulate
the vulnerability of metastatic lesions to immune
ACKNOWLEDGMENTS
surveillance, and understanding these factors
should assist in the development of immuno- K.H. was supported by a Postdoctoral Fellow-
therapies for patients with metastatic disease. ship from the Swiss National Science Founda-

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Downloaded from http://perspectivesinmedicine.cshlp.org/ on July 17, 2023 - Published by Cold Spring Harbor Laboratory Press
A. El-Kenawi et al.
tion (P400PM_183881). B.R. was supported by
the Florida Breast Cancer Foundation, the Flo-
rida Department of Health Bankhead-Coley
Cancer Research Program (8BC02), and spon-
sored research agreements with Tesaro, Inc.
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The Immune Microenvironment and Cancer Metastasis

Asmaa El-Kenawi, Kay Hänggi and Brian Ruffell

Cold Spring Harb Perspect Med 2020; doi: 10.1101/cshperspect.a037424 originally published online
September 9, 2019

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Asmaa El-Kenawi, Kay Hänggi and Brian Ruffell

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