Professional Documents
Culture Documents
549
Macrophage polarization:
tumor-associated macrophages as a
paradigm for polarized M2
mononuclear phagocytes
Alberto Mantovani, Silvano Sozzani, Massimo Locati, Paola Allavena and Antonio Sica
Mononuclear phagocytes are versatile cells that can express different functional
programs in response to microenvironmental signals. Fully polarized M1 and M2
(or alternatively activated) macrophages are the extremes of a continuum of
functional states. Macrophages that infiltrate tumor tissues are driven by
tumor-derived and T cell-derived cytokines to acquire a polarized M2 phenotype.
These functionally polarized cells, and similarly oriented or immature dendritic
cells present in tumors, have a key role in subversion of adaptive immunity and
in inflammatory circuits that promote tumor growth and progression.
Published online: 19 September 2002
Alberto Mantovani*
Istituto di Ricerche
Farmacologiche Mario
Negri, Via Eritrea 62,
I-20157 Milan, Italy.
Centro IDET, Institute of
General Pathology,
University of Milan,
Via Mangiagalli 31,
I-20133 Milan, Italy.
*e-mail: mantovani@
marionegri.it
Silvano Sozzani
Dept Biotechnology,
Section of General
Pathology and
Immunology, University
of Brescia, 25123 Brescia,
Italy.
Istituto di Ricerche
Farmacologiche Mario
Negri, Via Eritrea 62,
I-20157 Milan, Italy.
Massimo Locati
Centro IDET, Institute of
General Pathology,
University of Milan,
Via Mangiagalli 31,
I-20133 Milan, Italy.
Paola Allavena
Antonio Sica
Istituto di Ricerche
Farmacologiche Mario
Negri, Via Eritrea 62,
I-20157 Milan, Italy.
1471-4906/02/$ see front matter 2002 Elsevier Science Ltd. All rights reserved. PII: S1471-4906(02)02302-5
Review
550
M1
M2
Membrane receptors
Scavenger receptor A
Scavenger receptor B
CD163
MR
TLR2, TLR4
CD14
Fc-RII (CD23)
CD80, CD86
Cytokines
TNF-
IL-1
IL-1 ra
IL-6
IL-12
IL-10
Type I IFN
Cytokine receptors
IL-1 R type I
Decoy IL-1 R type II
Chemokines
CXCL9, CXCL10,
CXCL11
CCL17, CCL22
CCL24
CCL2, CCL3,
CCL4, CCL5
CXCL8
CCL18
CCL16
Chemokine receptors
CCR7
CCR2
CXCR1, CXCR2
Effector molecules
iNOS
arginase
ROI
IFN and LPS
IL-10
Review
Angiogenesis
Stroma
Fibroblast
Collagen
CXCL8
CXCL1,2
VEGF
FGF2
Monocyte
DC
TGF-
CCL2
CCL20
Fibrin
IL-10
TGF-
Tissue
factor
Recruitment
MMPs
CCL18
TAM
IL-4
IL-13
Survival
MMPs
IL-10
TGF-
Polarization
VEGF
Suppression
Countercurrent
invasion
CCL2
CCL5
Tr cell
Tumor
Growth
Progression
TRENDS in Immunology
Fig. 2. TAMs as polarized M2 macrophages. TAMs are a source and target for cytokines and
chemokines in the tumor microenvironment. These molecules and other local mediators (e.g. tissue
factor, MMPs) regulate tumor growth, progression and invasion, interaction with other components
of the stroma, and the activation and orientation of adaptive immunity. Abbreviations: DC, dendritic
cell; FGF, fibroblast growth factor; IL, interleukin; M-CSF, macrophage-colony stimulating factor;
MMP, matrix metalloproteinase; TAM, tumor-associated macrophage; TGF, transforming growth
factor; Tr, regulatory T; Tu, tumor; VEGF, vascular endothelial growth factor; vMIP, viral macrophage
inflammatory protein.
vMIPs
Tumor
Nave
T cell
Th2 cell
CCL22
CCL17
M-CSF
Growth
factors
Anergy
551
552
Review
Review
Macrophage
Plasmacytoid
DC
+
M-CSF, IL-10,
IL-6
Monocyte
IL-10, IL-6
TGF-,
VEGF
Tumor and
stromal cells
IL-10,
TGF-
IL-10 low
IL-12 high
MHC high
B7 high
Myeloid DC
Mature DC
TRENDS in Immunology
Fig. 3. Accumulation and differentiation of DCs in neoplastic tissues. Both myeloid and plasmacytoid
DCs are present in tumors. Cytokines produced by tumor cells or stromal elements promote the
differentiation of precursors into macrophages rather than DCs and block DC maturation.
Abbreviations: DC, dendritic cell; IL, interleukin; M-CSF, macrophage-colony stimulating factor;
TGF, transforming growth factor; VEGF, vascular endothelial growth factor.
NO,
TNF-
growth factors,
TNF-
chemokines
chemokines
VEGF, FGF2,
TNF-
TNF-, MMPs
Angiogenesis
Matrix
collagen, fibrin
Progression
Metastasis
IL-10, TGF-, PG
chemokines
Adaptive immunity
polarization, anergy, suppression
TRENDS in Immunology
Fig. 4. A simplified view of the role of TAMs in the immunobiology of tumors. Abbreviations:
FGF, fibroblast growth factor; IL, interleukin; MMP, matrix metalloproteinase; NO, nitric oxide;
PG, prostaglandin; TAM, tumor-associated macrophage; TNF, tumor necrosis factor;
TGF, transforming growth factor; VEGF, vascular endothelial growth factor.
http://immunology.trends.com
TAM
MMPs, TGF-
chemokines
553
554
Review
16
17
18
19
20
21
22
23
24
25
26
27
28
Review
53
54
55
56
57
58
59
60
61
62
555
2.q
9/7
10:
e 1
1 am
23
Vol.
9,
No.
06
71-49
N 14
ISS
464
423
pp.
et
edN
Bion.cMom
and
bm
http://immunology.trends.com
Please contact:
The Editor,
Trends in Immunology,
Elsevier Science London,
84 Theobalds Road,
London, UK WC1X 8RR.
(Fax: +44 (0)20 7611 4470)
Pag
e 1
N 14
71-49
06
2002
s
iew
rev
y
log
ws,
e ne muno
HIV
ry T
all th in im
DC s
ing
ss to nces
nic
ulato
acce ic adva
Gett leroge
reg
tif
y for
nolog t scien
cific
to
immu e lates
-spe
.com/ on th
Are
/bmn inion
gen
p:/
op
o
ed
it htt
Vis inform
Path
am
pp.
375
421
ISS
ber
em
Sept
ol.
mun
ds Im
Tren
ia
atch
kem
is)m
Leu its (m ing places?
re
s
s hid
atu
of it
i-m
s
find
out
cell
sem
42
No.
8,
/02
xd
/02
02 Vo
l. 23
Sep
xd
Tren
ds
9:4
6/8
IT
2.q
Imm
unol
. Au
gust
20
Pag
200
GM
-C
and SF in
Th1
T
imm h 2
uno
Ste
p
mc
a
t
ells
hol
T-ce
for
ll co
ogy
stim thymic
ulati
reg
Bio
e
Med
Net
bmn.c
om
on
nera
tion
Vis
it
and http:/
inform /bmn
.co
ed
opini m/im
mu
on
no
on
the logy for
lates
t sc access
ientif
to
ic ad all th
vanc e ne
es in ws,
immureview
nolog s
y