DOI: 10.1126/science.

1190310
, 697 (2010); 328 Science
Carlene L. Zindl and David D. Chaplin
Tumor Immune Evasion
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www.sciencemag.org SCIENCE VOL 328 7 MAY 2010
697
PERSPECTIVES
M
any types of human tumors can
suppress the immune system to
enhance their survival. Some
tumor cells escape immune detection by
decreasing the expression of certain anti-
gen-presenting proteins at their surface, ren-
dering them invisible to cytotoxic T lympho-
cytes ( 1). But more often, tumors secrete
proteins that inhibit effector T cell responses
and promote the production of regulatory T
cells that suppress immune responses ( 2).
On page 749 of this issue, Shields et al.
( 3) identify another mechanism by which
tumors deceive the immune system. Cer-
tain melanomas can reorganize their stromal
microenvironment (the supportive connec-
tive tissue) into structures similar to lym-
phoid tissue of the immune system. This
ingenious reconstruction recruits and main-
tains immune regulatory cells that promote
tolerance and tumor progression.
Lymphoid tissue inducer (LTi) cells con-
tribute to the organogenesis of secondary
lymphoid tissues (lymph nodes and Pey-
ers patches) during mammalian develop-
ment ( 4, 5). These cells express members
of the tumor necrosis factor (TNF) cytokine
familyTNF, lymphotoxin (LT
1

2
), and
TNF-related activation-induced cytokine
(TRANCE). Together, these factors boost
the expression of chemokines and adhesion
molecules by stromal organizer cells dur-
ing fetal development ( 6). As the stromal
cells (tissue supporting cells) of the lymphoid
organ develop, they express adhesion mol-
ecules and chemokines (such as CXCL13
and CCL21) that support their stable interac-
tions with fetal LTi cells, as well as recruit LTi
cells, B cells, and T cells into the developing
tissue ( 7). Ultimately, this localized stromal
cell activation results in an organized, com-
partmentalized lymphoid organ that regulates
immune responses.
In adult mammals, LTi cells direct the reor-
ganization of stromal cells into tertiary lym-
phoid structures (lymphoid tissuelike struc-
tures found at nonlymphoid sites) under con-
ditions of persistent inammation or infec-
tion ( 8, 9). Shields et al. show that mouse and
human melanomas expressing the chemokine
CCL21 can recruit LTi cells. This results in
reorganization of the tumors stroma and the
recruitment of CD4
+
regulatory T cells, mye-
loid-derived suppressor cells, and other leu-
kocytes (see the gure). Because other sig-
nals in addition to CCL21 contribute to sec-
ondary and tertiary lymphoid tissue develop-
ment, it may be that other tumor types that use
these signaling pathways may induce stroma
reconstruction as well.
Secondary and tertiary lymphoid tissues
provide a favorable environment for activating
humoral and cellular immunity. But if a tumor
thrives when it escapes immune responses,
then why would it create surroundings with
characteristics of an immune system tissue?
The association of lymphoid structures with
tumors underscores the fact that lymphoid
tissues can both activate and down-regulate
immune effector pathways. For example,
stromal cells in lymph nodes present antigen
to CD8
+
T cells in a way that induces toler-
ance rather than activation ( 10). Additionally,
lymphoid tissues provide an environment in
which nave T cells, in the presence of trans-
forming growth factor (TGF-), become
regulatory T cells, further favoring the sup-
pression of effector T cell functions. Thus, by
mimicking the functions of secondary or ter-
tiary lymphoid tissues, lymphoid tissuelike
stromal structures created by tumors can pro-
mote immune tolerance and suppression.
Do melanoma cells directly block or
reduce the differentiation of nave T cells into
effector T cells, or do they act indirectly by
recruiting immunoregulatory antigen-pre-
senting cells into the lymphoid tissuelike
structures? Shields et al. observed that B cells
were not recruited to the site of melanoma
cell accumulation. Because B cells can prime
T cells in secondary lymphoid tissues, per-
haps their absence reduces immune activa-
tion within the tumor-induced stroma. Alter-
natively, TGF- produced in the tumor may
alter local macrophage populations, resulting
Tumor Immune Evasion
IMMUNOLOGY
Carlene L. Zindl
1
and David D. Chaplin
2
Malignant cells can induce the formation
of lymphoid tissuelike structures that help
the tumor evade host immunity.
1
Department of Pathology, University of Alabama at Bir-
mingham, Birmingham, AL 35294, USA.
2
Department of
Microbiology, University of Alabama at Birmingham, Bir-
mingham, AL 35294, USA. E-mail: dchaplin@uab.edu
Tumor cells
CCL21
Tumor creates a suppressive
environment and evades
the immune response
Tumor environment changes;
lymphoid structure forms
Blood
vessel
Tumor secretes a high
concentration of CCL21
Fibroblast
LTi
T
reg
MDSC
M2
Cell recruitment
CCR7
Lymphoid stroma formation. Mouse tumor cells expressing the chemokine
CCL21 recruit lymphoid tissue inducer (LTi) cells, regulatory T (T
reg
) cells, and
myeloid-derived suppressor cells (MDSCs). LTi cells direct the reorganization
of local stroma into lymphoid tissuelike structures that support T
reg
cells and
MDSCs and lead to immune tolerance of the tumor. M2 macrophages secrete
extracellular matrix proteins that promote stromal stability. C
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Published by AAAS

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7 MAY 2010 VOL 328 SCIENCE www.sciencemag.org 698
PERSPECTIVES
in a switch from classically activated, phago-
cytic, and proinammatory M1 macrophages
to alternatively activated, poorly phagocytic,
and anti-inflammatory M2 macrophages
that secrete extracellular matrix proteins ( 11,
12). This raises the question of whether fac-
tors normally produced by tumors alter the
type of antigen-presenting cells in the tumor
microenvironment in ways that inuence the
immune response and promote stromal sta-
bility. Understanding how tumor-induced
changes in the stroma influence different
immune cells will be important for determin-
ing ways to modulate these structures.
The involvement of LTi cells in the lym-
phoid tissuelike structures observed by
Shields et al. suggests that the cytokine
LT
1

2
may act to increase the expression of
the chemokine CCL21. This may be impor-
tant because LT
1

2
-dependent structures are
generally plastic. Thus, the lymphoid tissue
like structures should be reprogrammable by
modulating LT
1

2
signaling, as has been
observed in stromal compartments of the
mouse spleen ( 13). Understanding the extent
to which tumor-induced lymphoid tissue
like structures are plastic will go a long way
toward determining if blocking CCL21 and/
or LTi cell function can disrupt immune toler-
ance of the tumor-induced structures, thereby
releasing host immunity to aid in eliminating
the malignant cells.
References
1. M. Meissner et al., Clin. Cancer Res. 11, 2552 (2005).
2. E. M. Shevach, Nat. Med. 10, 900 (2004).
3. J. D. Shields, I. C. Kourtis, A. A. Tomei, J. M. Roberts,
M. A. Swartz, Science 328, 749 (2010); published online
25 March 2010 (10.1126/science.1185837).
4. R. E. Mebius, P. Rennert, I. L. Weissman, Immunity 7, 493
(1997).
5. H. Yoshida et al., Int. Immunol. 11, 643 (1999).
6. D. Kim et al., J. Exp. Med. 192, 1467 (2000).
7. K. M. Ansel et al., Nature 406, 309 (2000).
8. F. Aloisi, R. Pujol-Borrell, Nat. Rev. Immunol. 6, 205
(2006).
9. T. Cupedo et al., Immunity 21, 655 (2004).
10. J. W. Lee et al., Nat. Immunol. 8, 181 (2007).
11. A. Mantovani et al., Trends Immunol. 23, 549 (2002).
12. A. Sica et al., Cancer Lett. 267, 204 (2008).
13. C. L. Zindl et al., Immunity 30, 408 (2009).
10.1126/science.1190310
Cometary Dust in the Laboratory
PLANETARY SCIENCE
Larry R. Nittler
Comparison of micrometeorites collected in
space and the Antarctic snow provides insight
into the early solar system.
M
uch of our understanding of early
solar system history comes from
the laboratory study of extrater-
restrial materials, especially meteorites from
the asteroid belt, as these are by far the most
readily available. However, it has long been
recognized that icy bodies in
the outer solar system might
contain a better-preserved
record of the earliest stages
of solar system formation
than can be found in even
the most primitive asteroi-
dal meteorites. This is sup-
ported by laboratory studies
of tiny (<50 m diameter)
meteoritesinterplanetary
dust particles or IDPscollected
by aircraft in the stratosphere.
Thought to originate at least in
part from comets, IDPs exhibit
highly primitive features ( 1, 2).
Two reports, one by Matzel et
al. (3) and one by Duprat et al.
(4) on page 742 of this issue, take
advantage of the availability of
relatively less studied primitive materials
samples obtained by the Stardust mission
from comet Wild 2 and Antarctic micromete-
orites (AMMs)to glean information about
the early solar system.
In 2006, NASAs Stardust returned solid
samples similar in size to IDPs ( 5) (see the
gure, panel A). Much less attention has been
paid to intermediate-sized AMMs obtained
by ltering melted Antarctic snow and/or ice
( 6). AMMs are in the size range (hundreds
of micrometers) that dominates the ux of
extraterrestrial materials incident on Earth,
but particles of this size are the most suscep-
tible to strong modication or destruction
by heating during atmospheric entry. How-
ever, prior work has shown that some AMMs
have survived their fall to Earth relatively
unscathed ( 6) and sample a broader range of
parent bodies, likely including comets ( 7),
than do the larger meteorites.
A major surprise came from the initial anal-
ysis of the Stardust samples from Wild 2. The
cometary dust was similar in many ways to
materials found in primitive meteorites ( 8), in
particular the abundance of high-temperature
phases, which must have formed in the inner
regions of the solar system and been subse-
quently transported outside the orbit of Nep-
tune. The high-temperature material included
grains similar to (but much smaller than) cal-
cium- and aluminum-rich inclusions (CAIs)
( 9), the oldest known solids in meteorites, and
chondrules ( 10), round silicate objects that
dominate many primitive meteorites. Matzel
et al. report the rst search for extinct
26
Al in
a grain from Wild 2, nicknamed Coki. The
radioisotope
26
Al (half-life = 730,000 years)
was homogeneously distributed in the early
inner solar system ( 11), and its abundance in
various meteoritic samples, inferred from its
decay product (stable
26
Mg), can thus be used
to infer relative chronological information
with high time resolution. Samples formed C
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Department of Terrestrial Magnetism, Carnegie Institution
of Washington, 5241 Broad Branch Road, NW, Washington,
DC 20015, USA. E-mail: lnittler@ciw.edu
10 m
B
Sample collection. (A) Dust sample captured in an
aerogel matrix during NASAs Stardust mission to
meet with comet Wild 2; the Coki grain studied by
Matzel et al. ( 3) is circled. (B) Researchers collect-
ing snow near CONCORDIA research station at Dome
C, Antarctica (75S, 123E). Melting and sieving of
this snow provided numerous micrometeorites (e.g.,
inset), including the ultracarbonaceous ones dis-
cussed by Duprat et al. ( 4).
0.5 mm
A
Published by AAAS

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