Reviews

Patrolling the vascular borders:

platelets in immunity to infection
and cancer
Florian Gaertner 1
* and Steffen Massberg 2
*
Abstract | Platelets are small anucleate cellular fragments that are released by megakaryocytes
and safeguard vascular integrity through a process termed ‘haemostasis’. However, platelets
have important roles beyond haemostasis as they contribute to the initiation and coordination
of intravascular immune responses. They continuously monitor blood vessel integrity and tightly
coordinate vascular trafficking and functions of multiple cell types. In this way platelets act as
‘patrolling officers of the vascular highway’ that help to establish effective immune responses to
infections and cancer. Here we discuss the distinct biological features of platelets that allow them
to shape immune responses to pathogens and tumour cells, highlighting the parallels between
these responses.

Coelomic circulation
The circulatory system of the
main body cavity.
Haemolymph
Fluid that circulates in the
interior of the arthropod body
that is analogous to the blood
in vertebrates.
1
Institute of Science
and Technology Austria,
Klosterneuburg, Austria.
2
Medizinische Klinik und
Poliklinik I, Klinikum der
Univerität München,
Munich, Germany.
*e-​mail: florian.gaertner@
ist.ac.at; steffen.massberg@
med.uni-​muenchen.de
https://doi.org/10.1038/
s41577-019-0202-z
Innate immunity comprises evolutionarily conserved
host defence mechanisms that can be traced back to
simple organisms, such as multicellular protozoans. For
example, the sentinel cells of the slug-​forming social
amoeba Dictyostelium discoideum can recognize and
phagocytose invading bacteria, or trap bacteria within
extracellular traps in a process requiring the Toll/IL-1
receptor domain-​containing protein tirA1,2. However,
the increasing body size and structural complexity of
multi­cellular organisms requires more diversified defence
systems. In this context, one of the major biophysical con-
straints facing larger organisms is the maximal diffusion
length permitting cellular exchange of gases, supply of
nutrients and disposal of metabolic waste3. To overcome
this, internal transport and exchange systems evolved to
provide bulk flow delivery of substances to and from each
cell in the body3. The coelomic circulation evolved to locally
transport fluids within mesothelial-​lined body cavities,
such as the pericardial, pleural and peritoneal cavities. In
addition, blood vascular systems emerged in the vast
majority of coelomates to provide bulk fluid transport
throughout the body3. In contrast to some invertebrates,
all vertebrates possess a closed circulatory system; in
adult humans, this is carpeted by approximately 1 × 1013
to 6 × 1013 endothelial cells and covers a surface area of
about 1–7 m2 (ref.4). This enormous surface is required
for sufficient blood supply throughout the body, and
maintenance of its integrity is a matter of survival. If a
vessel springs a leak, the organism runs the risk of severe
blood loss, tissue malperfusion and death. Damage to
the blood–tissue barrier can also provide a portal for
entry for pathogens that may use the vascular highways
to spread within the organism. Consequently, the evolu-
tion of circulatory systems also required the emergence
of special surveillance strategies to detect injury, restore
vascular integrity and prevent tissue infection.
In many invertebrates, these pivotal tasks are per-
formed by only one type of cell that circulates within the
blood or haemolymph. For example, the Atlantic horse-
shoe crab (Limulus polyphemus) — a marine arthropod
whose origin can be traced back more than 400 million
years — has circulating amoebocytes that establish
innate immune responses against invading pathogens
but also adhere and aggregate at breaches of the exo-
cytoskeleton to initiate coagulation and form plugs5.
In mammals, these classical haemostatic functions are
fulfilled by platelets. However, it is now realized that plate­
lets also have important immunological roles that extend
beyond their haemostatic functions and that they can
contribute to immunity to infections6–8 and cancer9.
Despite representing two very distinct disease enti-
ties, infection and cancer share important common
pathophysiological principles10,11. Similarly to invading
pathogens, malignant tumours that grow in size and
spread within the organism have to break down tissue
barriers, including blood vessel walls, during haemato­
genous metastasis. The elicited tissue damage serves as
an innate danger signal, initiating the recruitment of
circulating immune cells, and acute inflammation fre-
quently precedes the development of protective adap-
tive immune responses in cancer12. However, sustained
inflammation can also contribute to tumorigenesis13.
Indeed, more than 150 years ago pathologists noted the
similarities between tumour stroma and chronic wounds

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Reviews
Box 1 | Megakaryopoiesis and thrombopoiesis
In endomitosis, megakaryocytic progenitors undergo repetitive cycles of DNA
replication without dividing, accumulating up to 64 times the normal amount of DNA166.
Polyploid megakaryocytes enlarge and develop an extensive membrane system, the
open canalicular system, which serves as a reservoir for platelet production166.
Once megakaryopoiesis is completed, the now mature megakaryocytes can enter
thrombopoiesis. Residing at strategic positions within the vascular niches of the bone
marrow or extramedullary organs, including the spleen and the lung, megakaryocytes
gain access to the circulation by protruding thick extensions167 into the vasculature,
which further elongate in a microtubule-​dependent manner168, ultimately becoming
thinner; these are referred to as ‘proplatelets’17,30,169,170. These proplatelets release
fragments into the bloodstream, which further divide to form 5,000–10,000 platelets
per megakaryocyte171. The cytoplasmic and nuclear remnants of megakaryocytes then
undergo apoptosis and are most likely removed by phagocytes172. Both excessive and
diminished platelet counts can cause life-​threatening conditions, such as thrombotic
or bleeding disorders. Consequently, megakaryopoiesis and thrombopoiesis need
to be tightly regulated to maintain platelet homeostasis. Importantly, immediate
replenishment of the circulating platelet pool can be achieved by either increasing
the pool of platelet-​generating megakaryocytes (accelerated megakaryopoiesis) or
augmented release of platelets into the circulation (accelerated thrombopoiesis).
(reviewed in ref.14). Their observations lead to the con-
cept of ‘tumours as chronic, non-​healing wounds’, which
highlights the potential role of classical players in wound
healing — such as fibrinogen and platelets — in host
responses to tumours15.
Consequently, host immune responses to infection
and cancer share important, evolutionarily conserved,
pathophysiological principles that are linked to haemo­
stasis. In particular, the dissemination of pathogens
or cancer cells from a primary lesion, as well as their
interaction with the immune system, is dependent on
platelets and platelet-​driven processes. In this Review,
we will highlight novel mechanistic insights into the
physiology of platelets that may provide a framework to
explain the parallels seen during disease progression in
infection and cancer.
Inflammation and platelet production
Inflammatory mediators regulate megakaryopoiesis
Anucleate platelets are a unique feature of the mammal­
ian haemostatic system. While non-​mammalian verte-
brates generate thrombocytes (the nucleated counterpart
of platelets) by conventional proliferation and matu-
ration of their progenitors, mammalian platelets are
cytoplasmic fragments derived from megakaryocytes5
(Box 1). Recent findings demonstrate that inflammatory
mediators are major regulators of platelet production,
thereby compensating for the increased immediate need
for platelets during infection and inflammation16,17.
Recent studies suggest the existence of platelet-​biased
haematopoietic stem cells (HSCs) that rapidly generate
megakaryocytes during acute platelet loss18–20. These
HSCs are characterized by a lineage-​negative, SCA1+
Thrombopoietin
KIT+CD150+CD48−VWF+ phenotype and were shown
(TPO). A glycoprotein hormone
produced by the liver and to undergo rapid cell cycle entry on acute depletion
kidney. TPO binds to and of circulating platelets and in response to increased
activates TPO receptor plasma levels of thrombopoietin (TPO)18. TPO induces
(CD110) on haematopoietic mitochondrial activation in HSCs and primes direct
stem and progenitor cells,
which is necessary for
differentiation into the megakaryocyte lineage21.
megakaryocyte proliferation Pro-​inflammatory cytokines are known to drive mega­-
and maturation. karyopoiesis in conjunction with TPO in vitro22, but the
748 | DECEMBER 2019 | volume 19
population of megakaryocyte progenitors that respond
to inflammatory stimuli in vivo was discovered only
recently. Stem-​like megakaryocyte-​committed progen-
itors (SL-​MKPs) share many features with multipotent
HSCs during homeostatic conditions and are main-
tained in a primed but quiescent state, thus contributing
little to steady-​state megakaryopoiesis16. However, acute
inflammation associated with infection drives rapid
maturation of SL-​MKPs, resulting in enhanced platelet
production. Increased expression of megakaryocyte-​
associated proteins was seen in SL-​MKPs in response
to various inflammatory mediators, including lipopoly-
saccharide (LPS), poly(I:C) and tumour necrosis factor
(TNF)16. This suggests a common role of SL-​MKPs in
inflammation-​triggered megakaryopoiesis, although it
remains to be determined how steady state and emer-
gency megakaryopoiesis are spatiotemporally organized
within the bone marrow niche.
Megakaryopoiesis in cancer
Thrombocythaemia (defined as a platelet count of more
than 450,000 per microlitre) is a hallmark of many
types of cancer, including lung, colon, breast, pan-
creatic, kidney and gynaecological cancers (recently
reviewed in ref.9). Increased platelet counts are also a
predictor of cancer in patients with occult malignancy23.
Elevated platelet counts in patients with cancer are
often accompanied by unexplained thrombotic events
that precede the diagnosis of an occult malignancy or
appear concomitantly with the tumour — this is known
as Trousseau’s syndrome. Multiple, likely overlapping,
mechanisms have been demonstrated to underlie
Trousseau’s syndrome24, including tumour cell produc-
tion of procoagulant mucins or microparticles contain-
ing tissue factor (also known as coagulation factor III).
However, the molecular basis of the accelerated mega-
karyopoiesis seen in Trousseau’s syndrome is still not
well defined. Similarly to sites of infection, the tumour
microenvironment is a rich source of cytokines that are
both locally active and released into the circulation and,
as such, are responsible for many systemic manifestations
of cancer25. IL-6 is a cytokine with a wide range of bio-
logical activities and is a potent inducer of megakaryo­
poiesis22,24. In an experimental model of ovarian cancer,
it was shown that carcinoma-​derived IL-6 triggered the
production of TPO in the liver, thereby accelerating
platelet production26. Importantly, tumour-​derived IL-6
and hepatic TPO also correlated with thrombocytosis
in a cohort of patients with ovarian cancer. Treatment
with an anti-​IL-6 antibody significantly reduced plate-
let counts in tumour-​bearing mice and in patients with
epithelial ovarian cancer26. Together, these findings show
that pro-​inflammatory cytokines involved in acute and
chronic inflammation may also provide a molecular
mechanism underlying paraneoplastic thrombocytosis.
Consequently, common principles may underlie the
altered megakaryopoiesis that is seen during cancer and
during infection (Fig. 1). In addition, megakaryocytes
provide niches for HSCs, but also for leukaemic stem
cells in the bone marrow, suggesting that they could be a
novel target in the treatment of malignant haematological
disorders (Box 2).
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 Reviews

• Megakaryopoiesis involved in leukocyte and HSC trafficking29, has been

• Thrombopoiesis
IFNα, TNF,
LPS, IL-6, IL-1α TPO
Liver
Thrombocytosis
IL-6
Infection/
TPO inflammation Platelet activation Cancer
Platelet consumption Trousseau’s
DIC syndrome
(thrombosis)
Thrombocytopenia
(bleeding)
Fig. 1 | Disturbance of platelet homeostasis in cancer and infectious diseases.
Infectious diseases (left side of figure) and cancer (right side of figure) trigger peripheral
platelet activation that eventually leads to detrimental thrombotic events, referred to
as ‘disseminated intravascular coagulation’ (DIC) in the case of infection or Trousseau’s
syndrome in cancer. Peripheral consumption of circulating platelets in turn results in
severe thrombocytopenia associated with haemorrhage. This leads to increases in
serum levels of thrombopoietin (TPO) that trigger platelet production to replenish the
circulating platelet pool. In addition, prothrombopoietic cytokines released at sites of
infection or in the tumour microenvironment further fuel the production of platelets,
eventually causing thrombocytosis and thus increasing the risk of thrombosis. IFNα,
interferon-​α; LPS, lipopolysaccharide; TNF, tumour necrosis factor.
Inflammatory mediators regulate thrombopoiesis
Inflammatory mediators also regulate thrombopoiesis.
For example, IL-6 has been shown to support proplatelet
formation22 and IL-1α initiates megakaryocyte rupture
as a mechanism of emergency platelet production27.
The inflammatory chemokine CC-​chemokine ligand 5
(CCL5), which is secreted on platelet activation, has
recently been shown to trigger proplatelet formation in
a CC-​chemokine receptor 5 (CCR5)-dependent man-
ner, suggesting a direct feedback between peripheral
platelet consumption and reactive platelet production
in the bone marrow28. In addition, the sphingolipid
sphingosine 1-phosphate, a biolipid predominantly
shown to support proplatelet formation both in vitro
and in vivo30. Although the number of known factors
triggering thrombopoiesis is still limited, it is intriguing
to note the prominent role of inflammatory mediators,
likely contributing to altered platelet production during
infection and cancer.
TPO
Immune sensing of vascular inflammation
Recruitment of platelets to sites of infection
In the bloodstream, platelets are found at the highest
densities close to the vessel wall, referred to as ‘platelet
margination’31. This puts platelets in a position to con-
stantly scan the vasculature by transiently binding to
or rolling over vessel wall components, including extra-
cellular matrix proteins, crawling or resident intra­
vascular immune cells and endothelial cells32–34. These
interactions allow platelets to quickly respond to early
local signs of infection6 and tumorigenesis9 (Fig. 2).
Unperturbed endothelial cells are covered by an
~0.5-μm-​thick carbohydrate-​rich layer with a net nega­
tive charge — the endothelial glycocalyx35. The glyco­
calyx physically prevents platelet adhesion and leukocyte
recruitment, thus playing a central role in maintaining
vascular integrity and homeostasis36. However, vari-
ous clinical conditions, including infection and sepsis,
are associated with glycocalyx degradation. Following
infection, endothelial cells can be activated directly —
for example, through sensing of pathogens by Toll-​like
receptors (TLRs) — or indirectly following the local
release of inflammatory mediators by tissue-​resident
macrophages37. Activation of endo­t helial cells with
LPS triggers the exocytosis of secretory lysosomes con-
taining proteolytic, hydrolytic and glycolytic enzymes
that initiate patchy endothelial glycocalyx degrada-
tion38. At the same time, Weibel–Palade bodies are
released that contain an array of proteins, peptides and
cytokines, including P-​selectin and the adhesive pro-
tein VWF. In contrast to the antiadhesive properties of
the glycocalyx in the steady state, a recent study sug-
gests a proadhesive function of the glycocalyx during

Box 2 | Megakaryocytes support HSCs in the bone marrow

Megakaryocytes not only generate platelets but also act as niche cells in the bone marrow compartment, where they
modulate the function of haematopoietic stem cells (HSCs). Perivascular megakaryocytes have been shown to colocalize
with transplanted HSCs as well as with endogenous HSCs, and host megakaryocytes facilitate donor HSC engraftment
after lethal irradiation173–175. With use of a genetic mouse model of diphtheria toxin-​induced megakaryocyte depletion,
it was recently shown that megakaryocytes that physically interact with HSCs within the bone marrow are required for
maintenance of HSC quiescence during homeostasis, in a process depending on transforming growth factor-​β1
(TGFβ1) and platelet factor 4 (PF4; also known as CXCL4)174,175. However, in response to stress, such as chemotherapy,
megakaryocytes can also release activating factors such as fibroblast growth factor 1 (FGF1), which transiently dominates
over TGFβ1 inhibitory signalling and supports HSC population expansion175. Consequently, megakaryocytes are the first
reported haematopoietic cell type that can serve as HSC-​derived niche cells to dynamically regulate HSC function. Indeed,
platelet-​biased HSCs, identified by von Willebrand factor (VWF) expression, are highly enriched in megakaryocyte niches,
and depletion of megakaryocytes selectively expands VWF+ HSC populations, highlighting the direct communication that
occurs between progenitors and their progeny within the megakaryocytic lineage176. The critical role of megakaryocytes
in maintaining HSC quiescence is further supported by the observation that large megakaryocytes accumulate in close
association with clusters of granulocyte–macrophage progenitors (cGMPs) during bone marrow regeneration, where they
secret quiescence-​enforcing signals to re-​establish homeostasis177. Indeed, depletion of megakaryocytes caused persisting
cGMP formation and prevention of HSC return to quiescence. Importantly, these findings may also provide an explanation
for dysregulated cGMP formation in leukaemia177 and identify the megakaryocytic niche as a potential novel target in the
treatment of leukaemia and related haematological disorders.

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Reviews

↑ Adhesion receptors
↑ Adhesive proteins Leukocyte
(e.g. VWF, P-selectin, Endothelial cell extravasation
E-selectin, ICAM1, activation (TLRs)
αvβ3 integrin, tissue factor) Angiogenesis
↓ Antiadhesion (glycocalyx) (e.g. VEGF) Infection
↓ Secretion of pro-inflammatory
mediators (e.g. CCL2, IL-8)

CD40L Physical
sealing
Platelet Platelet receptors:
e.g. GPIb, P-selectin, Permeability vascular Vascular integrity,
Activation tone (e.g. IL-1 β, prevention or
GPIIb, GPVI, CLEC2,
Blood flow CD44 histamine, serotonin) haemorrhage

Rolling/tethering/adhesion

Secretion and
microparticle
Activation release Secretion

VEGF

Detachment of Formation of
Endothelial cell perivascular cells premetastatic
activation Leukocyte niches
Cancer extravasation
↑ Adhesion receptors Tumour
↑ Adhesive proteins angiogenesis
(e.g. VWF, P-selectin, (VEGF)
ICAM1, αvβ3 integrin,
tissue factor)

Fig. 2 | Platelet–endothelial cell interaction during infection and cancer. Platelets are equipped with a plethora of
adhesion receptors that immediately engage with the inflamed endothelium during infection and cancer, thereby
reinforcing platelet activation. Activated platelets in turn release their granule cargo containing proangiogenic factors
that further activate endothelial cells, support angiogenesis and regulate vascular permeability and vascular tone.
In addition, platelets safeguard vascular integrity by sealing microlesions at sites of leukocyte extravasation. Together with
leukocytes, platelets may release prometastatic factors that prime the vascular bed for tumour cell seeding, thus forming
a premetastatic niche. CLEC2, C-​type lectin-​like receptor 2; GP; glycoprotein; ICAM1, intercellular adhesion molecule 1;
TLRs, Toll-​like receptors; VEGF, vascular endothelial growth factor; VWF, von Willebrand factor.

inflammation; heparan sulfates from the glycocalyx bind
VWF, thereby stabilizing large VWF fibres and likely
supporting the recruitment of platelets to the activated
endothelial surface39. In addition, there is upregulated
expression of other adhesion molecules, such as inter­
cellular adhesion molecule 1 (ICAM1) and αvβ3 integrins,
culminating in enhanced platelet rolling and intensi-
fied platelet–endothelial interactions40,41. Activation of
endothelial cells also drives the expression of tissue fac-
tor, thus promoting coagulation and consecutive forma-
tion of fibrin strands that provide an additional platform
for platelet recruitment42.
During the adhesion process, platelets are activated
and expose or release signalling molecules that further
boost endothelial cell activation. For example, activated
platelets express CD154 (also known as CD40L) and
this stimulates CD40-expressing endothelial cells to
upregulate expression of E-​selectin, vascular cell adhe-
sion molecule 1 (VCAM1) and ICAM1, as well as pro-
moting endothelial cell secretion of pro-​inflammatory
mediators such as CCL2 and IL-8 (ref.43). Despite being
anucleate, platelets have the ability to synthesize proteins
de novo from stored RNA templates44. Platelet synthesis
of IL-1β is upregulated by inflammatory stimuli, and
platelet-​derived IL-1β increases endothelial activation
and permeability, thereby supporting the recruitment
of leukocytes45. Indeed, platelet shedding of IL-1β-​rich
microparticles contributes to increased vascular perme-
ability in dengue virus infection46. Together, this recipro-
cal activation of platelets and endothelial cells amplifies
inflammation at sites of infection. However, although
platelets promote increased vascular permeability and
leukocyte egress during acute inflammation, they also
release factors that support endothelial barrier function
and vascular integrity, as we discuss in more detail later.
Platelet recruitment to the tumour vasculature
The signalling cascades that recruit platelets to the
endothelium are not unique to infection; they are also
seen at tumour sites (Fig. 2). Solid tumours that have
grown beyond a critical size of a few cubic millime-
tres need to increase vascularization to receive oxygen
and nutrients required for their high energy demand
and growth, or to dispose of metabolic waste. Tumour

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angiogenesis is fostered by a combination of stimu-
latory signals within the tumour microenvironment
that prompts changes in multiple cell types47. Tumour
cells release cytokines and growth factors such as vas-
cular endothelial growth factor (VEGF) that activate
endothelial cells and stimulate their sprouting and
proliferation. The activated endothelium upregulates
expression of VWF39, P-​selectin48,49, αvβ3 integrins50,51
and tissue factor52, thereby promoting local recruitment
of platelets. In addition, sustained release of proangi-
ogenic factors increases endothelial permeability
and causes the detachment of perivascular cells from
mature blood vessels, thus compromising vessel integ-
rity and triggering the recruitment of platelets to sites
of exposed basement membrane53. Activated platelets
in turn release their stored pools of angiogenic and per-
meability factors into the tumour microenvironment
to further fuel vascular remodelling and inflammation.
As the newly formed vessels are exposed to persistent
stimulatory signals within the tumour microenviron-
ment, they remain immature and leaky47. Persisting
inflammation, aberrant blood vessels, plasma exudate
and the accumulation of platelets and immune cells
led to the description of cancer as ‘wounds that do not
heal’15. Platelets recruited to the tumour vasculature and
releasing proangiogenic cargo thus initially fuel vascular
permeability. However, one has to consider that at the
same time platelets also safeguard the tumour micro­
vasculature and prevent further aggravation as they sup-
port vascular integrity by plugging endothelial breaches
and releasing angiostatic factors, such as angiopoietin 1
(refs 54,55) . Indeed, it was shown that proangiogenic
and antiangiogenic proteins are separated into distinct
types of α-​granules in platelets and megakaryocytes that
undergo selective release on stimulation56. Accordingly,
human platelets stimulated with PAR4 agonists selec-
tively released antiangiogenic endostatin-​containing
granules, whereas PAR1-mediated activation of plate-
lets liberated proangiogenic VEGF-​bearing granules56.
Consequently, selective inhibition of distinct platelet
functions such as adhesion to inflamed blood vessels
or granule secretion may provide therapeutic options
to interfere with aberrant angiogenesis during inflam-
mation and tumorigenesis. In addition, platelets have
the ability to sequester tumour-​derived angiogenesis
regulatory proteins, such as VEGF, and redistribute
them within the organism. While this platelet function
contributes to tumour metastasis57, analysis of the plate-
let cargo may also serve as an early diagnostic tool for
detecting the presence of tumours in vivo before they
are macroscopically evident58.
Platelet sensing of target cells
Platelets sense pathogens at sites of vascular invasion
The innate immune system has to mediate the imme-
diate recognition, phagocytosis and killing of invasive
pathogens while discriminating self-​tissues from non-​
self59. To cope with this demanding task, evolutionary
selection over millions of years equipped innate immune
cells with pattern recognition receptors (PRRs)60. PRRs
detect highly conserved pathogen-​associated molecu-
lar patterns (PAMPs) or damage-​associated molecular
NATuRe RevIeWs | IMMunology
Reviews
patterns (DAMPs) that are released by compromised or
damaged host cells60. Platelets are among the first cells
recruited to inflamed or injured endothelial cells and
are well positioned to sense PAMPs and DAMPs gener-
ated at these sites (Fig. 3). Accordingly, platelets express
functional TLRs, and transcripts encoding TLR1–TLR10
have been identified in platelets; TLR expression is more
abundant in platelets in women than in platelets in
men61–63. Besides PRRs, platelets also express receptors
that allow them to directly interact with pathogens. Once
activated, platelets secrete various immunomodulatory
and antimicrobicidal factors stored in their α-​granules64.
Platelet antimicrobial factors include defensins (such as
human β-​defensin 2), thymosin β4, derivative antimicro­
bial peptides (such as fibrinopeptides A and B cleaved
from fibrinogen), thrombocidins (proteolytic derivatives
of CXCL7) and kinocidins (for example, CXCL4, CXCL7
and CCL5), which are a group of proteins that function
as both chemokines and microbicidal effector proteins64.
Platelets make use of their armoury in fighting and killing
a plethora of pathogens, as we discuss next65,66.
Platelet responses to viruses. Platelets express a variety
of receptors that mediate their interaction with viruses,
including integrins, surface lectins and TLRs67. The
binding and uptake of viral particles triggers platelet
activation, degranulation and interaction with neutro-
phils, including neutrophil-​mediated phagocytosis of
platelets67. In addition, the formation of virus-​dependent
immune complexes promotes platelet activation68. This
leads to the clearance of platelets from the circulation
and, together with impaired platelet production caused
by many viruses, may result in severe thrombocyto­
penia. Consequently, haemorrhagic fever is a hallmark of
many viral infections69. Nevertheless, even though some
viruses may hijack platelets for their own replication70
and misguide platelet adhesion71 or even cause platelet
destruction46, it has been demonstrated that platelets in
turn have direct and indirect antiviral activities that
promote the clearance of viral pathogens67. For exam-
ple, although TLR7-mediated activation of platelets
by encephalomyocarditis virus triggers the binding
of platelets to various leukocyte subsets and peripheral
platelet consumption, platelet activation is eventually
essential for host survival during infection72. The data
therefore suggest a potentially beneficial role of platelet–
virus interactions in host defence against viral infections.
Platelets also control virus infection by secreting chemo­
kines that interfere with receptor-​mediated uptake into
host cells; this can reduce viral loads in HIV, for example73.
Activated platelets release CCL3 and CCL5 (ref.74), which
have been identified as major HIV-​suppressive fac-
tors produced by cytotoxic T lymphocytes75 and might
thus contribute to platelet-​mediated virus defence.
In addition, platelet release of defensins, which impair
bacterial growth76, can also drive antiviral activity77.
Platelet responses to bacteria. Many bacteria use the vas-
cular system as a dissemination route within the host.
When bacteria enter the mammalian bloodstream, they
encounter platelets, which have evolved multiple recep-
tors that mediate binding to invading microorganisms.
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a Invasion of
e
blood vessels/
tissue injury Infection

Platelet Extravasation CTC

• Acute phase proteins activation
Haemostasis • Bacterial proteins
(PAMPs)
• Chemokines
Encapsulation Secretion of, PMPs Fibroblast
Platelet e.g., TGFβ,
PGE2, LPA miR-24
Leukocyte recruitment

EMT

Physical MSC
b Platelet–pathogen interactions Macrophage
platelet–
Pathogen killing tumour cell
Leukocyte contact Tumour cell
Antimicrobial factors
recruitment (PMPs, kinocidins) Pathogen
binding
Secretion
Activation
e.g. GPIb/
TLR GPIIb
f Platelet–cancer cell interactions
PAMP e.g. fibrinogen Tumour cell-induced
Secretion Activation
C3 platelet aggregation Tumour cell
binding
Secretion
e.g. ADP, P-selectin
Amplification ATP
Pathogen Mucins
engulfment • Proangiogenic
Pathogen ‘covercyte’ • Protumorigenic GPIb/
coating CLEC2 GPIIb etc.
Podoplanin αvβ3 integrin

MHC-1 (mimicry)
Protection
Adaptive from shear
Leukocyte immunity stress CTC TGFβ
c Initiation of adaptive immunity Tumour cell IFNγ
cloaking
Expansion
of cytotoxic
CD8+ T cells NKT cell

Antigen
presentation CD40L Metastasis
CD40 (CD154)

CD4+ T cell B cell

DC T cell • Class-switching g Metastasis
to IgG
Cytokine • GC formation
production Splenic red pulp Leukocyte
recruitment
Platelet and tumour
microparticles
• Dissemination
• Clearance CTCs
Fibrin Secretion
Thrombin Leukocyte
d Pathogen capture and clearance recruitment

CTC ↓ Endothelial
Leukocyte adhesion barrier

Platelet Fibrin
migration ROS ↑ YAP1
Aggregation Transmigration/
Tumour- extravasation
educated
NETs platelets
Kupffer cell
Survival
Bacterial Neutrophil
trapping Hepatic Leukocyte
microcirculation
Premetastatic/early
metastatic niche formation

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 Reviews

◀ Fig. 3 | Platelet interaction with invasive pathogens and cancer cells. a | Platelets are infection, thereby preventing bacterial entry into the
recruited to sites of infection, where they shape subsequent host immune responses by circulation and dissemination through vascular routes.
interacting with leukocytes but also by directly binding to invading pathogens. b | The In addition to bacterial trapping, the attachment of
consequence of platelets binding to pathogens largely depends on the type of pathogen platelets to bacteria may support the targeted delivery
concerned and may involve engulfment or direct killing of the invader. Pathogens
of antimicrobicidal substances from platelet granules and
resisting the platelet attack may exploit platelets as a protective shield against other
immune cells. c | Platelets also shuttle pathogens within the blood and escort them to promote bacterial cell death82. However, S. aureus can
the spleen, where they are recognized by splenic dendritic cells (DCs), which initiate the resist the initial platelet attack and instead subvert the
adaptive immune response. Platelets also directly interact with T cells to enhance B cell host response by using the platelet ‘coat’ to hide from
maturation and antibody class-​switching. d | In the liver, intravascular macrophages the immune system. Together with the recruitment of
(Kupffer cells) bind blood-​borne pathogens. Platelets immediately form aggregates coagulation factors, these platelet–bacteria interac-
around Kupffer cell-​bound bacteria and support their uptake. Platelets recruited to tions are presumed to be important in the development
the inflamed microvasculature can actively migrate to scan their microenvironment. of biofilms observed during bacterial endocarditis83.
During sepsis, platelets migrate within liver sinusoids to capture bacteria and bind them on Although in the short term this adaptation seems to be
their surface. Platelet-​bound bacteria trigger neutrophil activation (leading to reactive advantageous for the bacteria, sustained platelet activa-
oxygen species (ROS) production) and NETosis, which is associated with the release
tion and fibrin binding reinforces thrombus formation84,
of neutrophil extracellular traps (NETs), which may in turn serve as a platform for the
trapping and killing of pathogens. Activated leukocytes also initiate fibrin formation, ultimately leading to the death of the host, thus leaving
which serves as an adhesive platform for platelets and also traps circulating bacteria. the bacterium unable to continue the infectious cycle.
e | Platelets adherent at sites of tumour growth secret protumorigenic growth factors Indeed, it has been shown that S. aureus also evolved
(such as transforming growth factor-​β (TGFβ), prostaglandin E2 (PGE2) and lysophosphatidic strategies to inhibit platelet activation, which might
acid (LPA)) that trigger epithelial-​to-mesenchymal transition (EMT) and foster vascular be advantageous in certain scenarios79,85. The case of
invasion. Platelets as well as platelet microparticles (PMPs) can leave the blood vessels S. aureus highlights the complexity of the multifaceted
and are found within the tumour stroma, where they may directly interact with tumour interactions between platelets and bacteria, which com-
cells or other cells in the tumour microenvironment, such as mesenchymal stem cells plicates the development of specific antiplatelet thera-
(MSCs) and macrophages. f | Platelets adhere to circulating tumour cells (CTCs) that pies for the treatment of infections. Nevertheless, several
enter the bloodstream and form aggregates, covering their surface. The platelet coat
studies suggest that modulation of platelet–bacteria
may serve as a protective barrier against the mechanical forces of the flowing blood and
interactions could provide a promising therapeutic
as a shield against attacks by natural killer T cells (NKT cells). In addition, platelets secrete
protumorigenic factors and equip tumour cells with adhesion receptors that promote option for the treatment of life-​threatening diseases such
metastasis at distant organ sites. g | Platelet-​mediated fibrin formation and NETosis as endocarditis86, pneumonia87 and sepsis81,88,89.
supports metastatic seeding of CTCs within the microvasculature. The recruitment of As outlined earlier, platelets possess an impressive
leukocytes by platelets may also contribute to premetastatic/early metastatic niche toolset to interact with different types of pathogen.
formation. In addition, secretion of tumour-​educated platelets facilitates transmigration Most of these interactions were identified in suspension
and survival of CTCs. GC, germinal centre; GP, glycoprotein; IFNγ, interferon-​γ; MHC-​I, in vitro by co-​incubation of platelets and bacteria in dif-
MHC class I; PAMPs, pathogen-​associated molecular patterns; TLRs, Toll-​like receptors. ferent ratios to control the frequency of their interactions.
The situation in vivo, however, is far more complex, and
Platelets can bind to bacterial surface proteins either spatiotemporal coordination of platelet–bacteria inter-
directly or indirectly through plasma proteins — such actions at sites of infection or within the vasculature are
as fibrinogen or VWF — that interact with bacteria. only poorly understood. While random interactions may
Platelets also interact with bacterial toxins or secreted certainly provide one possibility to encounter pathogens
products78. The consequences of platelet–bacteria bind- within the bloodstream, efficient clearance of blood-​
ing are diverse and can result in complete or incomplete borne bacteria requires non-​random, coordinated inter-
platelet activation or inhibition of platelet activation79 actions. Within liver sinusoids, for example, Kupffer cells
depending on the bacterial strain and/or the bacterial serve as docking platforms for both platelets and bacteria,
product involved. thus reinforcing the likelihood of physical interactions
The ability to trigger platelet activation is a well-​ that can in turn support Kupffer cell-​mediated phago-
known feature of Staphylococcus aureus infection. cytosis of bacteria32. Once recruited from the flowing
Activated platelets strongly bind to S. aureus either blood, platelets may perceive additional guidance cues
directly or indirectly, using plasma proteins such as for searching for and catching pathogens at the inflamed
fibrinogen. Platelet pseudopods wrap around the bac- vasculature. Indeed, platelets express receptors for the
teria but, in contrast to phagocytes, it remains unclear if chemotactic complement components C3a and C5a as
platelets actually phagocytose bacteria or if they instead well as multiple chemokines that are generated at sites
trap them on their cell surface within the highly folded of infection64,74,90. Although chemotactic molecules were
plasma membrane, referred to as the ‘open canalicular shown to support platelet activation in various patho-
system’80. At sites of primary infection, platelets may use physiological conditions74,91,92, it remains controversial
their ability to catch and trap bacteria to prevent their dis- whether adherent platelets are capable of directional
semination within the bloodstream and to present them migration towards chemotactic stimuli in a manner
to intravascular phagocytes81. This platelet function has described for leukocytes93. A study by our own group
been shown to support the clearance of and the immune recently identified platelet migration at sites of bacterial
response to blood-​borne infection within the liver micro- infection and showed platelets use this migratory ability
circulation in vivo32,81 (see Fig. 3). Nevertheless, further to efficiently capture pathogens and trap them on their
studies are needed to confirm that platelet-​mediated surface81 (Fig. 3). Although this study clearly indicates
bacterial trapping does indeed constitute a first line a pathophysiological role of platelet migration in vivo,
of defence against invasive pathogens at primary sites of it remains unknown whether random exploration by

NATuRe RevIeWs | IMMunology volume 19 | DECEMBER 2019 | 753

Reviews
Ticagrelor
A reversible inhibitor of the
ADP receptor subtype P2Y12
used to treat patients with
acute coronary syndromes.
P2Y12
A subtype of the platelet ADP
receptor family that triggers
strong platelet activation.
754 | DECEMBER 2019 | volume 19
migrating platelets is sufficient to establish platelet–
bacteria interaction or whether platelets use directional
cues to chase their prey. Indeed, several earlier studies
suggested chemotaxis in the context of vascular injury
and inflammation94–97. Platelet chemotaxis in vitro was
also observed in response to N-​formyl peptides, which
are chemotactic molecules released by bacteria98.
Platelet responses to primary tumours
Platelets adhere to the tumour vasculature and accu-
mulate at sites of primary tumours, thereby influenc-
ing tumour growth and metastasis (Fig. 3). Accordingly,
platelet inhibition with ticagrelor or deficiency of P2Y12
on platelets significantly reduced growth of orthotopic
tumours and was beneficial in mouse models of ovar-
ian cancer99. Several, protumorigenic growth factors
have been identified within the platelet cargo, including
transforming growth factor-​β1 (TGFβ1)9. The prolifer-
ative effects of platelets do not necessarily require phys-
ical tumour cell–platelet interaction100. Consequently,
platelets may exert their protumorigenic functions even
before tumours have gained access to the circulation.
Tumour cells access the systemic circulation by enter-
ing blood vessels either directly or indirectly by using
draining lymph nodes as a hub for further dissemina-
tion101,102. To achieve this task, individual tumour cells
must detach from the primary tumour and adopt a
migratory and invasive phenotype — a process referred
to as ‘epithelial-​to-mesenchymal transition’ (EMT)103.
EMT involves cellular loss of adherens junctions and
conversion from a polygonal, epithelial morphology to
a spindly, fibroblastic morphology, expression of matrix-​
degrading enzymes, increased motility and heightened
resistance to apoptosis103. These adaptations do not arise
in a strictly cell-​autonomous manner but are largely
influenced by factors released from cells in the sur-
rounding tumour microenvironment104, including mes-
enchymal stem cells105 and macrophages106. Platelets have
also been shown to contribute to this process. Indeed,
activated platelets and platelet-​derived microparticles
have been identified within the tumour microenviron-
ment, outside tumour-​associated blood vessels26,107–109.
Although the mechanisms of platelet extravasation
remain unclear, it was recently shown that their associa-
tion within primary tumour cells facilitates EMT108. For
example, platelet-​derived TGFβ and physical platelet–
tumour cell interactions synergize to upregulate tumour
cell expression of mesenchymal markers, such as snail,
vimentin, fibronectin, plasminogen activator inhibitor 1
(PAI1) and matrix metalloproteinase 9 (MMP9), while
downregulating the expression of E-​cadherin; together,
these changes promote a migratory and invasive tumour
cell phenotype110. In addition, several other platelet-​
released mediators have been suggested to play a role in
tumour EMT, including prostaglandin E2 (PGE2) and lyso­
phosphatidic acid111,112. Although most studies suggest
that platelets promote a more invasive and promalignant
tumour cell phenotype and drive disease progression,
a recent report described a tumour-​suppressive func-
tion of platelets. The authors of that study showed that
platelet-​derived microparticles infiltrate solid tumours
and transfer the microRNA miR-24 to tumour cells,
which led to mitochondrial dysfunction and inhibition
of tumour growth113.
Invasion of the vasculature causes tumour cells to
leave the supportive tumour microenvironment and
experience the hostile conditions of flowing blood114.
High shear stresses at the luminal side of blood vessels
can physically harm cancer cell integrity and the blood
also contains large numbers of immune cells, such as
natural killer (NK) cells, that are capable of detecting
and killing circulating tumour cells (CTCs). Platelets
are among the first cells to interact with intravascular
cancer cells. Platelets bind to CTCs and form aggre-
gates around them almost immediately after they have
entered the bloodstream. CTCs actively augment aggre-
gate formation by secreting platelet-​activating ADP108,
expressing tissue factor or releasing prothrombotic and
procoagulant microparticles115–117. Platelets ‘cloak’ CTCs
and provide a shield against the shear stress of flowing
blood118 and protection from NK cells119. In addition to
physically encasing CTCs from NK cells, platelets can
inhibit NK cell cytotoxicity by transfer of MHC class I
molecules onto the surface of tumour cells120. Moreover,
platelets also actively inhibit NK cell antitumour activ-
ity through the TGFβ-​mediated downregulation of the
receptor NKG2D, which is a major recognition receptor
for the detection and elimination of transformed cells121.
Together, these studies clearly show that tumour
cells are capable of hijacking platelets to subvert the host
immune response against cancer. As platelet–tumour
cell interactions constitute a major pathophysiological
mechanism underlying disease progression, targeting
platelets may be a promising strategy for the treatment
of cancer9,122. In addition, the strong binding of platelets
to CTCs makes them an ideal cargo system for targeted
delivery of anticancer drugs123.
Platelet shuttling functions
Having entered the bloodstream, pathogens and tumour
cells face a barren environment where they are exposed
to high mechanical forces of the bloodstream as well to
intravascular immune cells. Consequently, both patho-
gens and CTCs seek to quickly escape the vasculature,
leading to pathogen dissemination and metastatic spread
in distant tissues and organs. We next discuss how plate-
let shuttling of pathogens and tumour cells affects these
disease processes (see Fig. 3).
Platelet shuttling of pathogens
Bacteraemia causes life-​threatening diseases, includ-
ing sepsis, infectious endocarditis and meningitis, and
bloodstream infections rank among the most com-
mon causes of death. Consequently, fast clearance of
blood-​borne bacteria in parallel to the development
of long-​lasting adaptive immunity is a pivotal task of the
immune system. Platelet binding to intravascular patho­
gens has a major role in these processes and predeter-
mines the journey of bacteria throughout the organism.
Blood-​borne pathogens are predominantly cleared by
specialized intravascular innate immune cells within
the liver sinusoids, the Kupffer cells, which express PRRs
that trigger capture of pathogens124,125. However, hepatic
host defence relies on the interplay of both cellular and
www.nature.com/nri

Neutrophil extracellular
traps
Web-​like structures consisting
of extracellular DNA strands
decorated with antimicrobial
proteins such as histones and
neutrophil proteases.
NATuRe RevIeWs | IMMunology
Reviews
humoral components of the blood126. Platelets are central can be detected. This process, referred to as ‘premeta-
coordinators in this scenario, as they not only directly static niche formation’, involves the recruitment of bone
bind and trap bacteria but also support leukocyte effector marrow-​derived leukocytes, including haematopoie-
functions. Platelets activated by TLR ligands rapidly bind tic progenitor cells, macrophages and monocytes, by
to leukocytes, and in neutrophils this triggers signalling soluble pro-​inflammatory factors produced by the pri-
events leading to the generation of reactive oxygen spe- mary tumour133–135. Mechanistically, prometastatic leuko­
cies and the release of neutrophil extracellular traps88,127. cytes pave the way for CTCs by promoting angiogenesis
Neutrophil extracellular traps in turn bind and activate and extravasation as well as by supporting survival and
coagulation factors, thereby promoting fibrin forma- growth of metastatic tumour cells135,136.
tion, which further enhances bacterial trapping and It remains unclear if and how platelets contribute to
serves as a platform for the recruitment and activation this process. However, recent studies have shown that
of additional platelets — a process termed ‘immuno- platelets are capable of taking up factors secreted by
thrombosis’84,89,128. During sepsis, platelet-​triggered for- tumour cells in vitro and in vivo137 and can even adopt an
mation of neutrophil extracellular traps in the liver and altered morphology as a result138. Indeed, platelets were
lungs increases the capacity of these immunocompetent found to take up proangiogenic cytokines from aggres-
organs for trapping and fighting blood-​borne patho- sively growing tumours and deliver them to indolent
gens88. Together these findings clearly demonstrate the tumour cells at distant sites, thereby supporting tumour
key role of platelets in orchestrating innate immunity to angiogenesis and proliferation57. Therefore, platelets
blood-​borne infections. may act as a long-​range delivery system potentially
However, for some infections to become fully con- involved in the manifestation of the systemic tumour
trolled, fast phagocytosis and immediate killing must be macroenvironment25.
accompanied by pathogen-​specific adaptive immunity, Platelets bound to tumour cells not only safeguard
such as the activation of cytotoxic T cells129. The latter CTCs within the bloodstream but also actively sup-
requires cross-​presentation by antigen-​presenting cells, port their seeding and outgrowth at distant organ
such as dendritic cells, which preserve antigen depots sites. Indeed, platelets are involved in all steps of the
to induce lasting adaptive immunity. Platelets bind to metastatic cascade, from initial CTC arrest to coloni-
complement-​opsonized bacteria in the bloodstream, zation139,140. CTCs bind to platelets and hijack platelet
thereby mediating the rapid clearance of these bacte- adhesion receptors, such as P-​selectin and the plate-
ria by Kupffer cells124. Some platelet-​bound bacteria let αIIbβ3 integrin, thereby supporting the adhesion
remain longer in the circulation and are shuttled to and firm arrest of the tumour cells at the endothelium139.
the spleen, where they are available to splenic CD8α+ For example, platelet-​expressed P-​selectin has been
dendritic cells to promote antibacterial cytotoxic T cell shown to specifically promote metastasis of melanoma
immunity130. Consequently, platelets not only support cells to the lung141. In contrast, liver metastasis was not
the fast clearance of bacteria within the liver32 but also affected by platelet P-​selectin in the same model and
promote the induction of specific antibacterial immu- was actually enhanced when platelet counts were exper-
nity130. The spleen, which hosts approximately one-​third imentally reduced141. Therefore, platelets may shuttle
of circulating platelets, may support these responses CTCs to organ-​specific sites141. Apart from direct inter-
by bringing together platelets, antigen-​presenting actions with CTCs, platelets can further support tumour
cells and lymphocytes to reinforce their interaction meta­stasis by promoting coagulation, weakening the
and to establish a platelet-​mediated adaptive immune endothelial barrier and producing growth factors (Box 3).
response (Fig. 3). Importantly, recent findings show that
MHC class I-​expressing megakaryocytes can process Platelets regulate leukocyte functions
and cross-​present antigens on their surface, thereby Regulation of leukocytes at sites of infection
triggering CD8+ T cell activation and proliferation131. Activated platelets interact with leukocytes during all
Megakaryocytes can transfer antigen-loaded MHC steps of the extravasation cascade and coordinate their
class I molecules to proplatelets during thrombopoiesis recruitment to sites of inflammation and infection
and may therefore spread this immunogenic information (Fig. 4). Immune-​sensing platelets activated by TLR ago-
through platelets131. Indeed, platelets have been shown nists do not form thrombi, but instead bind to blood-​
to present pathogen-​derived antigens to promote T cell borne leukocyte populations, including lymphocytes,
responses in vivo in an experimental cerebral malaria dendritic cells, monocytes, eosinophils, basophils and
mouse model132. neutrophils. This results in the formation of heterotypi­
cal platelet–leukocyte conjugates63. Platelet–leukocyte
Platelet shuttling of circulating tumour cells interactions are predominantly established by the bind-
Similarly to blood-​borne pathogens, CTCs can also ing of P-​selectin on activated platelets to PSGL1 (also
be trapped within the microvasculature of tissues. known as CD162) on leukocytes142. However, CD40–
From here, they may eventually extravasate to enter CD40L interactions and interaction of platelet glyco-
into the tissue parenchyma and form metastases. protein Ib or platelet-​expressed αIIbβ3 integrin with
It has recently become clear that these processes are not αMβ2 integrin on leukocytes also have a major role
random events but are instead coordinated by many (reviewed in ref.63). These interactions trigger leukocyte
tumour- and host-​derived factors25. Primary tumour-​ activation and integrin expression, thus priming the ini-
driven systemic processes have been identified that tiation of vessel wall adhesion143,144. Leukocytes may also
dictate the site of CTC seeding even before metastasis activate platelets145 and hijack adhesion receptors from
volume 19 | DECEMBER 2019 | 755
Reviews
Box 3 | Platelets support tumour metastasis
Regulation of coagulation
Accelerated coagulation and thrombocytosis have long been recognized as key
mechanisms supporting the progression of malignancy and associated with poor
prognosis24,164. Mice lacking fibrinogen or factor XIII show diminished metastasis165,178.
Both circulating tumour cells (CTCs) and platelets provide a platform for the initiation of
plasma coagulation by triggering the cleavage of enzymatically inactive prothrombin to
form active thrombin, eventually boosting fibrin formation116. Platelets and tumour cells
also release microparticles into the circulation that promote systemic coagulation116.
Chemokine production
On contact with CTCs, activated platelets release CXCL5 and CXCL7 and trigger the
rapid recruitment of neutrophils to platelet–CTC microthrombi179. In a mouse model
of colon carcinoma, neutrophils recruited to platelets and CTCs further enhanced
metastatic progression154,179. P-​selectin-mediated heterotypical interactions of platelets,
leukocytes and CTCs have been shown to activate microvascular endothelial cells at sites
of early metastasis180. Activated endothelial cells in turn secrete CCL5, which recruits
monocytes to the prometastatic niche180. Tumour cells themselves can also upregulate
their expression of chemoattractants to recruit prometastatic myeloid cells134,135.
Platelets may directly contribute to this process as they have been shown to shift the
gene expression profiles of tumour cells to a more metastatic phenotype110. Indeed,
platelets can induce a YAP1-dependent transcriptional programme in CTCs, which is
important for cancer cells to overcome anoikis (detachment-​induced apoptosis)181.
Effects on endothelial barriers and production of growth factors
Platelets can trigger specific signalling pathways in tumour cells that increase their
invasive potential and can also promote tumour cell trafficking across the vessel wall by
weakening the endothelial cell barrier. Platelets activated by CTCs release ATP from
their dense granules, which induces P2Y2-dependent signalling events that eventually
lead to the disruption of endothelial cell tight junctions182,183. In addition, platelets
indirectly support tumour cell transmigration by recruiting prometastatic leukocytes
capable of releasing permeability-​increasing cytokines and growth factors, such as
vascular endothelial growth factor (VEGF)114,135. VEGF is also released by activated
platelets and promotes angiogenesis, thereby facilitating colonization and outgrowth
of the initial metastatic seed184.
surface-​bound platelets to promote their adhesion to the
endothelium.
Platelets already deposited in blood vessels retain
their ability to bind and recruit leukocytes and assist their
extravasation by secreting cytokines and chemokines
as well as reinforcing adhesion, mainly via P-selectin–
PSGL1 interactions146. As such, platelets serve as dock-
ing platforms for leukocytes (reviewed in ref.63). In turn,
adherent leukocytes actively scan for circulating platelets
by extruding PSGL1-containing uropods into the vascu-
lar lumen; platelet binding to neutrophil uropods was
shown to support neutrophil activation and inflamma-
tory reactions in LPS-​triggered sepsis34. Activated plate-
lets74 also deposit CCL5 and CXCL4 on the surface of
endothelial cells at sites of tissue inflammation, thereby
instructing the intravascular crawling and extravasation
of inflammatory cells. Importantly, these platelet-derived
chemokines gain full functionality only by forming hetero­
Factor XIII dimers, and disruption of these functional interactions
A transglutaminase that inhibits inflammation147–149.
crosslinks and stabilizes the Although the findings described above indicate
fibrin meshwork
a pro-​inflammatory role of platelet–leukocyte inter-
Clopidogrel actions, recent findings suggest that platelets can also
An irreversible inhibitor of the cooperate with inflammatory cells to resolve inflamma-
platelet ADP receptor subtype tion150–152. Platelets expressing C-type lectin-like recep-
P2Y12 used clinically to prevent tor 2 (CLEC2; also known as CLEC1B) were found to
thrombotic events in patients
receiving percutaneous
negatively regulate pro-​inflammatory alveolar macro­
coronary intervention for phages and prevent excessive tissue damage in a model
coronary atherosclerosis. of LPS-induced lung injury151. The anti-inflammatory
756 | DECEMBER 2019 | volume 19
action of platelet CLEC2 was further demonstrated in
two mouse models of sepsis152. In addition, platelets were
found to protect mice from septic shock by inhibiting
macrophage-​dependent production of IL-6 and TNF153.
Therefore, platelets seem to have both pro-​inflammatory
and anti-​inflammatory roles during infection.
Regulation of leukocytes in the tumour
microenvironment
At neoplastic lesions, tumour-​infiltrating inflammatory
cells recruited from the blood can suppress antitumour
immune responses and support tumour growth and
metastasis154. Although platelets play an important role in
immune cell recruitment to sites of infection and meta­
stasis, their contribution to leukocyte recruitment to pri-
mary tumours remains unclear. On the basis of the data
discussed earlier, activated platelets within the primary
tumour vasculature might serve as adhesive docking
platforms and support leukocyte adhesion and trans-
migration by secreting pro-​inflammatory molecules.
However, this has not been demonstrated to date.
Although the role of platelets in leukocyte recruit-
ment to tumours remains to be established, recent
findings indicate that platelets may directly modulate
lymphocyte effector functions in the tumour micro­
environment. Platelets highly express glycoprotein A
rep­etitions predominant (GARP), which binds latent
TGFβ and converts it to its active form155. Indeed, in
a model of melanoma and colon carcinoma, platelet-​
intrinsic GARP was the most important pathway in
the systemic activation of TGFβ. TGFβ activated by
platelet-​expressed GARP dampened T cell function in
mice and suppressed adoptive T cell therapy for cancer.
By contrast, the efficacy of adoptive T cell therapy was
enhanced following platelet inhibition by aspirin and
clopidogrel156. This suggests that combining immuno-
therapies with use of antiplatelet agents could represent
a new paradigm for the treatment of cancer156. Indeed,
in transplant models of melanoma and breast cancer,
platelets were shown to facilitate the transport of anti-
bodies targeting the immune checkpoint molecule
programmed cell death 1 ligand 1 (PDL1) to residual
microtumours at the surgical site, and also to CTCs in
the blood, thereby reducing tumour recurrence and
metastasis, respectively157.
Maintenance of vascular integrity
As discussed, platelets can promote the extravasation
of activated leukocytes during infections and cancer.
However, they also help to maintain vascular integrity
during inflammation, and individual, non-​aggregated
platelets that are scanning the inflamed endothelium
or platelets that have ‘piggybacked’ onto migrating
leuko­cytes promote the immediate sealing of endo­thelial
microbreaches158 (Figs 1,4). Consequently, thrombo­
cytopenic mice experience microvascular bleedings in
various settings of sterile and non-​sterile inflammation,
including infection and cancer159.
Platelet glycoprotein VI (GP6) and CLEC2, which
are the only immunoreceptor tyrosine-​based activation
motif-​containing receptors present on mouse plate-
lets, are indispensable for engaging individual platelets
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 Reviews

at microvascular lesions that occur during immune
complex-​mediated skin inflammation158,160, in LPS-​
induced lung inflammation160 and following immuni-
zation with ovalbumin in Freund’s complete adjuvant161.
In addition, platelet αIIbβ3 integrin was also shown to
have a protective effect on the inflamed vasculature as
demonstrated in models of viral infection and brain
infarction162,163.
Besides physically plugging endothelial micro­
breaches, platelets can secrete soluble mediators that

a
Basophil Lymphocyte

Neutrophil
Eosinophil

Inflammation
Leukocyte
extravasation
Macrophage
Infection Monocyte

Podoplanin–
CLEC2

Secretion
Chemokines and TXA2
cytokines etc.
Extracellular P-selectin–PSGL1
Docking platform vesicles Assistance of
Adhesion receptors Arachidonic Vascular integrity intraluminal
acid crawling

b
↓ Permeability
Circulating heterotypical
• S1P
platelet–leukocyte
Red blood • Angiopoietin 1
aggregates
P-selectin–PSGL1 cell ↑ Permeability
CD40–CD40L ? • VEGF
TLRs Adhesion
• Serotonin

Tumour vasculature
Leukocyte
extravasation
TGFβ
Cancer
Cytotoxic
T cell
Inflammation/immunity
• Angiogenesis
• Proliferation
• Inhibition of senescence
• EMT

Neutrophil Lymphocyte
Monocyte

Fig. 4 | Platelets coordinate leukocyte trafficking across vessel walls
and modulate leukocyte functions. a | Platelets support all steps of
leukocyte extravasation during infection and inflammation (upper part).
Platelets bind to leukocytes to assist leukocyte rolling, adhesion and
intravascular crawling. They secrete chemokines to guide leukocytes to
sites of infection and serve as docking platforms to initiate their
transmigration. Platelets can also cooperate with inflammatory cells, such
as tissue-​resident macrophages, to resolve inflammation. In addition,
platelets that have ‘piggybacked’ onto leukocytes seal vascular
microbreaches caused by leukocyte recruitment. b | Although their
contribution to leukocyte recruitment to primary tumours remains largely
unknown, platelets can directly modulate lymphocyte effector functions in
the tumour microenvironment. In addition, platelets safeguard the tumour
vasculature and seal vascular breaches caused by extravasating leukocytes.
CLEC2, C-​type lectin-​like receptor 2; EMT, epithelial-​to-mesenchymal
transition; S1P, sphingosine 1-phosphate; TGFβ, transforming growth
factor-​β; TLRs, Toll-​like receptors; TXA2, thromboxane A2; VEGF, vascular
endothelial growth factor.

NATuRe RevIeWs | IMMunology volume 19 | DECEMBER 2019 | 757

Reviews

maintain the stability of the vasculature. They consti-
tutively express trophogens and release cytokines and
growth factors, such as angiopoietin 1 and sphingosine
1-phosphate, that preserve the structural and functional
integrity of the vascular endothelium164. Therefore, plate-
lets possess a versatile toolset that allows the maintenance
of vascular integrity in the steady state and during infection
and inflammatory conditions, including cancer165.
Conclusions
Platelets are the major effectors of haemostasis and have
evolved immune functions that help them control and
defend the mammalian vasculature against infection.
To achieve this, platelets use sophisticated machinery to
detect potential pathogen entry sites and to recognize
and eventually neutralize pathogen intruders. However,
these same evolutionarily conserved immune features of
platelets can have both positive and detrimental effects
in certain cancer settings. This makes platelets promising
targets for the development of novel therapeutic strate-
gies against infection and cancer. However, as a direct
consequence of platelet ‘multitasking’, the inter­ference
with global platelet function makes the net effect on host
fitness hard to predict. Consequently, a major goal of
future research will be to further dissect the molecu­lar
mechanisms that allow the specific fine-​tuning of plate-
let immune functions in order to effectively target them
in the clinic.
Published online 13 August 2019

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Acknowledgements
This study was supported by SFB914 (S.M.), SFB1123 (S.M.),
SFB1312 (S.M.) and the Deutsches Zentrum für Herz-​
Kreislaufforschung (S.M. and F.G.). F.G. received funding from
the European Union’s Horizon 2020 research and innovation
programme under Marie Skłodowska-​Curie grant agreement
no. 747687.
Author contributions
The authors contributed equally to all aspects of the article.
Competing interests
The authors declare no competing interests.
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Reviewer information
Nature Reviews Immunology thanks E. Josefsson and
the other, anonymous, reviewer(s) for their contribution to the
peer review of this work.
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