REVIEWS

Inhibitory B7-family molecules in the

tumour microenvironment
Weiping Zou* and Lieping Chen‡
Abstract | The B7 family consists of activating and inhibitory co-stimulatory molecules that
positively and negatively regulate immune responses. Recent studies have shown that human
and rodent cancer cells, and stromal cells and immune cells in the cancer microenvironment
upregulate expression of inhibitory B7 molecules and that these contribute to tumour immune
evasion. In this Review, we focus on the roles of these B7 molecules in the dynamic interactions
between tumours and the host immune system, including their expression, regulation and
function in the tumour microenvironment. We also discuss novel therapeutic strategies that
target these inhibitory B7 molecules and their signalling pathways to treat human cancer.

Tumour-associated antigens
(TAAs). Antigens that are
expressed by tumour cells.
These belong to three main
categories: tissue-
differentiation antigens, which
are also expressed by non-
malignant cells; mutated or
aberrantly expressed
molecules; and cancer testis
antigens, which are normally
expressed only by
spermatocytes and
occasionally in the placenta.
Myeloid-derived suppressor
cells
A population of cells that
comprises mature and
immature myeloid cells. They
are expanded and/or activated
during an inflammatory
immune response. Through
direct interactions and
secreted components, they
inhibit T‑cell function.
*Department of Surgery,
University of Michigan, Ann
Arbor, Michigan 48109, USA.
‡
Departments of Dermatology
and Oncology, Johns Hopkins
University School of Medicine,
Baltimore, Maryland 21231,
USA.
e-mails: wzou@med.umich.
edu; lchen42@jhmi.edu
doi:10.1038/nri2326
The specific function of an individual’s immune system
in different physiological and pathological settings is
regulated by the actions of opposing factors or sys-
tems. Common examples of this are the polarization of
T helper (TH) cells into TH1-cell and TH2-cell subsets
with opposing functions, and the balance between effec-
tor T‑cell activation and regulatory T‑cell activation. At
the molecular level, co-stimulatory members of the B7
family can have both inhibitory and stimulatory effects
on T‑cell activation.
An imbalance in immune regulation profoundly
affects tumour-specific T‑cell immunity in the cancer
microenvironment and can reshape tumour progression,
metastasis and immunotherapy in patients with cancer1. It
is well known that the lack of naturally induced immunity
specific for tumour-associated antigens (TAAs) is not simply
a passive process whereby adaptive immunity is shielded
from detecting TAAs1–9. It has been clearly shown that the
tumour microenvironment is comprised of dysfunctional
immune cells that are reprogrammed by active tumour-
mediated processes to evade tumour-specific immunity in
a highly effective manner. Three important mediators of
this evasion of tumour immunity that have been identi-
fied in the tumour microenvironment are: dysfunctional
antigen-presenting cells (APCs), including dendritic cells
(DCs), macrophages1,10 and myeloid-derived suppressor
cells11,12; regulatory T (TReg) cells13–16; and high levels of expres-
sion of inhibitory B7 molecules by APCs, stromal cells and
tumour cells1,17. The first two mediators have been spe-
cifically reviewed in the literature elsewhere1,10–13,15. In this
Review, we focus on inhibitory B7 molecules, and detail
their expression, regulation, function and therapeutic
relevance in the tumour microenvironment.
Inhibitory B7 molecules
T-cell activation and tolerance are not chance occur-
rences. Many molecules form an orchestrated system to
regulate the interactions between APCs and T cells. This
interaction is explained by the two-signal model, whereby
signal one is provided to the T-cell receptor of T cells by
the presentation of specific antigens on MHC molecules
expressed by APCs, and signal two is provided by the B7
family and other co-stimulatory molecules that APCs
use to direct and/or fine-tune T‑cell responses (FIG. 1).
The growing B7 family now comprises seven members,
which are CD80 (also known as B7.1), CD86 (also known
as B7.2), B7-DC (also known as PD‑L2 or CD273),
B7-H1 (also known as PD‑L1 or CD274), B7-H2 (also
known as ICOSL), B7-H3 (also known as CD276) and
B7-H4 (also known as B7S1 or B7x)17–19. Compelling
evidence indicates that B7 molecules not only provide
crucial positive signals to stimulate and support T‑cell
activation, but can also offer negative signals that control
and suppress T‑cell responses17,18. These negative signals
are largely provided by the newly identified B7-family
members B7‑H1 and B7‑H4.
CD80/CD86–CTLA4. CD80 and CD86 control T-cell
activation by binding to and signalling through two
receptors, CD28 and cytotoxic T-lymphocyte antigen 4
(CTLA4), that are expressed by T cells (FIG. 1). CD80
and CD86 are not classically considered as inhibitory
B7 molecules. However, on T‑cell activation, the expres-
sion of their inhibitory receptor, CTLA4, is induced
on T cells, and engagement of CTLA4 by CD80 and
CD86 can limit and decrease T‑cell activation. The
role of CTLA4 in controlling T‑cell activation and its

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REVIEWS
Regulatory T (TReg) cells
A T‑cell population that can
functionally suppress an
immune response by
influencing the activity
of another cell type.
Several phenotypically
distinct regulatory T‑cell
populations exist. The classic
regulatory T cells are
CD4+CD25+FOXP3+ T cells
known as TReg cells.
Two-signal model
The concept that both the
MHC–peptide complex
(signal 1) and co-stimulatory
signals delivered by B7-family
molecules expressed by
antigen-presenting cells
(signal 2) are required for T‑cell
activation. The absence of
signal 2 results in the induction
of T‑cell anergy or deletion.
Cytotoxic T‑lymphocyte-
antigen 4
(CTLA4). After engagement by
CD80 or CD86 on antigen-
presenting cells, CTLA4
signalling in activated T cells
induces cell-cycle arrest,
decreases cytokine production
and inhibits T‑cell responses.
CD4+CD25+ TReg cells
constitutively express CTLA4.
468 | june 2008 | volume 8 www.nature.com/reviews/immunol
APC T cell
CD80 CD28
CD86 CTLA4
MHC TCR
B7-DC ? the case and that herpes virus entry mediator is the
PD-1
B7-H1 CD80
B7-H2 ICOS
B7-H3 ? haematopoietic cells, but rarely by stromal cells and
B7-H4 ? encoding B7‑H1 and B7‑H4 is found in almost all tissues
IgV-like domain IgC-like domain
Figure 1 | The B7 family and antigen presentation to
T cells. Antigen-presenting cells (APCs) or APC-like cells
Nature
present a specific antigen on MHC Reviews |to
molecules Immunology
the T‑cell
receptor (TCR) of T cells. Members of the B7 family and
other co-stimulatory molecules are used to direct and/or
fine-tune T‑cell responses. The newly identified B7‑H1
and B7‑H4 molecules provide negative signals that
control and suppress T‑cell responses. Human tumour
cells and tumour-associated APCs express limited levels
of the stimulatory B7-family members CD80 and CD86,
and high levels of the inhibitory B7-family members
B7‑H1 and B7‑H4. This imbalance between the expression
of stimulatory and inhibitory B7 molecules might
contribute to tumour immune evasion in the tumour
microenvironment. CTLA4; cytotoxic T-lymphocyte
antigen 4; ICOS, inducible T-cell co-stimulator; PD-1,
programmed cell death 1.
therapeutic relevance have been reviewed elsewhere19
and are not discussed in detail here. CTLA4-specific
antibodies have recently entered clinical trials for the
treatment of various human cancers19.
B7‑H1. B7‑H1 was first cloned on the basis of its DNA
sequence homology to other B7 molecules belonging
to the immunoglobulin superfamily20. Programmed
cell death 1 (PD‑1; also known as CD279) has been
subsequently identified as a counter-receptor for B7‑H1
(Ref. 21) (FIG. 1), and B7‑H1 is therefore also known as
PD‑L1 to emphasize this receptor–ligand interaction21.
However, experimental evidence indicates that addi-
tional counter-receptor(s) other than PD‑1 can mediate
the functions of B7‑H1. In the absence of PD‑1 or if
binding to PD‑1 is blocked, B7‑H1 can have a stimula-
tory effect on T‑cell immunity17,20,22–24. Moreover, CD80
is an additional counter-receptor for B7‑H1 for the
inhibition of T‑cell responses25. To make the situation
more complicated, B7‑H1 can also function as a receptor
to transmit signals into T cells26 and tumour cells27. In
summary, B7‑H1 can act as both ligand and receptor to
execute immunoregulatory functions.
© 2008 Nature Publishing Group
B7‑H4. B7‑H4 was also identified by DNA sequence
homology to other B7 molecules28–30. B7‑H4 remains an
orphan ligand, although evidence indicates that a recep-
tor can be induced and could function on T cells28,30,31.
The currently known functions of B7‑H4 are exclusively
inhibitory and the effect of B7‑H4 might be mediated
by a single receptor. B- and T-lymphocyte attenuator
(BTLA) was initially proposed to be the receptor for
B7‑H4 (Ref. 32), but recent studies show that this is not
ligand for BTLA33–35.
Expression pattern
CD80 and CD86 have a restricted expression pattern,
being expressed mainly by professional APCs and
non‑haematopoietic cancer cells17,18. By contrast, mRNA
and most stromal and haematopoietic cells. This distri-
bution pattern indicates unique functions for these mol-
ecules in both lymphoid and non-lymphoid organs.
Expression of B7‑H1. The expression of mRNA encod-
ing B7‑H1 is abundant in many tissues and organs
in humans20,36 and mice21. A recent study indicates
that the phosphatase and tensin homologue (PTEN)–
phosphatidylinositol-3‑kinase pathway might be
important in the post-transcriptional regulation of
B7‑H1 cell-surface expression in tumours37. B7‑H1
protein is often expressed by activated cells including
T cells, B cells, DCs, monocytes/macrophages 20,21,23,
natural killer (NK) cells38, activated vascular endothe-
lial cells39, mesenchymal stem cells40 and cultured bone-
marrow-derived mast cells41. B7‑H1 is also found to
be expressed constitutively in immune-privileged sites
including the eyes and placenta42,43, which indicates
that B7‑H1 might inhibit self-reactive T cells or B cells
and therefore control inflammatory responses in these
tissues and organs.
Most human cancers tested so far express high levels
of B7‑H1 protein44 (TABLE 1). However, low or rare B7‑H1
expression is observed in most mouse and human
tumour-cell lines44. This might be owing to the lack
of the complete cancer microenvironment in cell lines
in vitro as these tumour-cell lines can upregulate B7‑H1
protein expression in response to cytokines44. Another
possibility, albeit less likely, is that certain molecular
profiles have been altered in established tumour-cell
lines during culture. Therefore, the results obtained
from established tumour-cell lines in vitro might
need to be interpreted carefully. In addition to tumour
cells, B7‑H1 protein expression has been observed
in human tumour-associated DCs 23,45, fibroblasts 46
and T cells47,48.
Expression of B7‑H4. Similar to B7‑H1, mRNA encoding
B7‑H4 is widely distributed in peripheral tissues28,49,50.
However, although the expression of B7‑H4 cell-surface
protein was detected in normal human epithelial cells of
the female genital tract, kidney, lung and pancreas, B7‑H4
protein was generally absent in other normal human
 REVIEWS

Table 1 | B7‑H1 expression in human cancers and its immunological, clinical and pathological associations*
Human cancer type B7‑H1+ cases/ Immunological, clinical and pathological associations Refs
total cases
Breast cancer 24/56 Number of B7‑H1+ T cells correlates with tumour size, stage and HER2‡ expression 36,44,48
Colon cancer 16/25 ND 36,44
Gastric cancer 45/105 B7‑H1 expression correlates with increased tumour size, metastasis and poor survival 36,89
Glioma 10/10 B7‑H1 expression by tumour cells inhibits T‑cell activation in vitro 125
Leukaemia 17/30 B7‑H1 expression by leukaemia cells has no effect on T‑cell activation in vitro 81
Lung cancer 86/87 B7‑H1+ regions of the tumour contain fewer T cells in non-small cell lung cancer 36,44,86
Melanoma 22/22 ND 44
Multiple myeloma 82/82 B7‑H1+ plasma cells inhibit T‑cell activation in vitro 126
Oesophageal cancer 18/41 B7‑H1 expression is associated with poor prognosis 88
Ovarian cancer 82/93 B7‑H1 expression by tumour cells is associated with a decreased number of T cells in 23,36,44,87
the tumour and poor prognosis. B7‑H1+ tumour-associated dendritic cells inhibit T‑cell
function.
Pancreatic cancer 20/51 B7‑H1 expression by tumour cells is associated with a decreased number of tumour 127
T cells and poor prognosis.
Peripheral T‑cell lymphoma 7/11 ND 36
Renal-cell carcinoma 130/196 B7‑H1 expression by tumour cells is associated with poor prognosis 44,85,128
Thymic neoplasm 28/34 ND 36
Urothelial cancer 142/268 B7‑H1 expression by tumour cells is associated with advanced stage, recurrence and 129,130
poor survival
*The data for each tumour type are assembled from more than one report. Some data have not been included in the table if less than 10 tumour samples were
reported for a particular type of human cancer. ‡HER2 (also known as ERBB2 or Neu) is a tumour-associated antigen that is expressed in about 25% of cases of breast
cancer. Vaccines against HER2 are being tested for cancer therapy in humans. Monoclonal antibodies specific for HER2 (such as trastuzumab (Herceptin;
Genentech/Roche)) are approved for the therapy of human breast cancer. ND, not determined.

Myeloid DCs
A subset of dendritic cells (DCs)
that are lineage-negative,
HLA-DR+CD11c+ (in humans)
mononuclear cells with a
monocytoid appearance.
Human myeloid DCs might be
derived from myeloid
precursors (for example,
monocytes, macrophages and
CD11c+ precursors).
Plasmacytoid DCs
A subset of dendritic cells (DCs)
that are lineage negative,
HLA-DR+CD11c– (in humans)
mononuclear cells with a
microscopic appearance
similar to plasmablasts.
Plasmacytoid DCs are the main
producers of type I interferon.
somatic tissues50. Nonetheless one study did observe
broad cell-surface expression of B7‑H4 protein on mouse
haematopoietic cells30. The cause of this interspecies
difference is unknown.
B7‑H4 is commonly detectable in the human cancer
microenvironment (TABLE 2). For example, human ovar-
ian cancers express high levels of B7‑H4 protein31,49,51–54,
and low levels of soluble B7‑H4 protein were found in
the sera from patients with ovarian cancer52,53. In addi-
tion to tumour cells, tumour-infiltrating macrophages31,55
and endothelial cells of small blood vessels56 in the can-
cer microenvironment are also found to constitutively
express B7‑H4.
In summary, the current data reveal broad expression
patterns of B7‑H1 and B7‑H4 protein in human tumours,
in contrast to their rare expression in normal tissues. These
data indicate that post-transcriptional regulation could
have a crucial role in the control of B7‑H1 and B7‑H4
protein expression in normal tissues and organs, and
that this regulatory mechanism is aberrant in tumours.
Further investigation of the regulatory mechanisms and
the signalling pathways leading to expression of B7‑H1
and B7‑H4 will generate important information for the
understanding of tumour immune evasion and provide
potential molecular targets for treating human cancers.
Regulation of expression
The tumour microenvironment contains a large number of
cytokines and inflammatory mediators1,57,58. Some of these
molecules can regulate the expression of B7‑H1 and B7‑H4.
Regulation of B7‑H1 expression. B7‑H1 expression can
be induced or maintained by many cytokines23,36,44, of
which interferon‑γ (IFNγ) is the most potent. Established
human tumour-cell lines rarely express B7‑H1 protein
on the cell surface, but high levels of B7‑H1 expression
can be induced by treatment with IFNγ in most of the
cell lines tested so far44. Consistent with this, IFNγ can
induce high levels of B7‑H1 expression by normal epi-
thelial cells, vascular endothelial cells39, proximal tubular
epithelial cells59 and myeloid DCs36,44. It is assumed that a
strong TH1-cell response can induce B7‑H1 expression
by APCs and other cells through IFNγ, and in turn main-
tain the threshold of T‑cell activation to avoid tissue and
organ damage. In addition to IFNγ, type I IFN can also
stimulate B7‑H1 expression by hepatocytes60, monocytes,
DCs61 and tumour cells (S. Wei, I. Kryczek, L. Chen and
W. Zou, unpublished observations). In this context, after
virus infection, tumour-associated plasmacytoid DCs
produce large amounts of type I IFN in vitro62, which
can in turn induce B7‑H1 expression23. Plasmacytoid
DCs preferentially induce TH2-cell responses in certain
situations63. Therefore, the expression of B7‑H1 could
potentially be stimulated in both TH1- and TH2-cell-
biased conditions, although the expression and relevance
of B7‑H1 expression in TH1- or TH2-cell-associated dis-
eases remains to be tested.
In light of its stimulatory effect on B7‑H1 expres-
sion, IFNγ could thus be a ‘double-edged sword’ in
tumour immunity. Whereas IFNγ could increase anti-
gen processing and presentation by upregulating the

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Table 2 | B7‑H4 expression in human cancers and its immunological, clinical and pathological associations*
Human cancer type B7‑H4+ cases/ Immunological, clinical and pathological associations Refs
total cases
Breast cancer (primary) 165/173 B7‑H4 expression is associated with lack of expression of progesterone receptor and HER2‡ 50,54
Breast cancer 240/246 ND 50
(metastatic)
Lung cancer 35/86 B7‑H4 expression is more common in patients with lymph-node metastasis 49,131
Ovarian cancer 202/216 B7‑H4 tumour-associated macrophages inhibit T‑cell activation and predict poor survival
+
31,49,51–55
Prostate cancer 120/823 B7‑H4 expression by tumour cells is associated with disease spread, recurrence and death 90
Renal-cell carcinoma 153/259 B7‑H4 expression by tumour cells is associated with poor survival 56
Uterine endometrioid 90/90 B7‑H4 expression by tumour cells is associated with weak T‑cell infiltration and high-risk 132
adenocarcinoma tumours
*The data for each tumour type are assembled from more than one report. Some data have not been included in the table if less than 10 tumour samples were
reported for a particular type of human cancer. ‡HER2 (also known as ERBB2 or Neu) is a tumour-associated antigen that is expressed in about 25% of cases of breast
cancer. Vaccines against HER2 are being tested for cancer therapy in humans. Monoclonal antibodies specific for HER2 (such as trastuzumab (Herceptin;
Genentech/Roche)) are approved for the therapy of human breast cancer. ND, not determined.

Indoleamine 2,3-
dioxygenase
(IDO). An intracellular haem-
containing enzyme that
catalyses the oxidative
catabolism of tryptophan.
Insufficient availability of
tryptophan can lead to T‑cell
apoptosis and anergy.
Arginase
An enzyme that converts
l‑arginine into l‑ornithine and
urea.
Danger signals
Agents that alert the immune
system to stress, usually by
interacting with Toll-like
receptors and other pattern-
recognition receptors, and
thereby promote the
generation of innate and
adaptive immune responses.
Danger signals can be
associated with microbial
invaders (exogenous danger
signals) or produced by
damaged cells (endogenous
danger signals).
expression of MHC molecules and components of the
antigen-processing machinery64, the effects of IFNγ on
B7‑H1 expression might downregulate T‑cell immu-
nity. This could explain, at least partially, why IFNγ
has not been effective as a therapeutic agent for most
human cancers. In addition, IFNγ has been shown to
stimulate the expression of indoleamine 2,3-dioxygenase
(IDO)65 and arginase66–68 on APCs. Such APCs could
suppress anti-tumour immune responses. Therefore,
it is not surprising that an increase in the number of
TAA-specific cytotoxic T lymphocytes (CTLs) does not
always translate into clinical regression of cancers69–72.
In addition, IFNγ was also found to mediate CD4+
T‑cell loss and impair secondary anti-tumour immune
responses after successful initial immunotherapy in
tumour-bearing mouse models73. As B7‑H1 expression
can be induced on APCs and multiple human epithe-
lial tumours, stimulation of B7‑H1 expression could be
a strategy used by the tumour to evade T‑cell‑mediated
tumour immunity.
Regulation of B7‑H4 expression. The regulation of
B7‑H4 expression has only been studied in the human
system. Interleukin‑6 (IL‑6) and IL‑10 stimulate B7‑H4
expression by monocytes, macrophages and myeloid
DCs. The DC‑differentiation cytokines, GM‑CSF
(granulocyte/macrophage colony-stimulating factor)
and IL‑4, decrease B7‑H4 expression by these cells
induced by IL‑6 and IL‑10 (Refs 31,55,74) (FIG. 2). IFNs
seem to have a minimal effect on the induction of B7‑H4
expression, in contrast to the induction of B7‑H1 expres-
sion44. In human ovarian cancer, tumour-associated TReg
cells trigger macrophages to produce IL‑6 and IL‑10, and
these cytokines in turn stimulate B7‑H4 expression by
APCs in an autocrine and/or paracrine manner55. High
levels of IL‑6 and IL‑10, but not GM‑CSF and IL‑4, are
detected in the ovarian tumour microenvironment.
Therefore, this dysfunctional cytokine network in the
tumour micro­environment enables APCs to express
B7‑H4. Interestingly, IL‑4, IL‑6, IL‑10 and GM‑CSF
have no regulatory effects on B7‑H4 expression on
tumour cells, which indicates that B7‑H4 on tumour
cells and B7‑H4 on APCs might be functionally distinct
and be differentially regulated31,55. Collectively, B7‑H1
and B7‑H4 are regulated by distinct mechanisms.
These differential regulatory patterns have important
implications in the generation and amplification of
tumour-specific immunity.
Evasion of tumour immunity
The physiological functions of inhibitory B7-family
members are to limit, terminate and attenuate T‑cell
responses, by which they prevent T‑cell hyperactivation
and avoid tissue and organ damage during immune
responses17,18. B7‑H1-deficient75,76 and B7‑H4‑deficient77
mice have been generated and reported in the pub-
lished literature. The inhibitory B7 molecules can be
induced in response to inflammation and potentially
to broader danger signals. It is therefore possible that
the expression of these molecules might contribute
to de novo cancer initiation and development. At the
present time, however, there is no evidence that these
molecules participate in carcinogenesis. However, these
inhibitory B7 molecules could suppress ongoing or
induced tumour immunity.
B7‑H1 expression by tumour cells. Initial studies
showed that transgenic expression of B7‑H1 on a B7‑
H1‑deficient mouse P815 mastocytoma cell line did not
change its tumourigenicity in naive mice44. However,
B7‑H1+ P815 tumour cells could continue to grow in
the presence of adoptively transferred P815-specific
T cells, which are sufficient to induce the regression of
wild-type P815 tumours44. This finding is consistent
with the observation that transfection of B7‑H1 into
a highly immunogenic P815 variant, which regresses
spontaneously in naive mice, led to progressive growth
of this line44. Similarly, in the presence of potent T‑cell
immunity, B7‑H1+ tumours are much more resistant
to T‑cell-mediated destruction in several mouse mod-
els78–80 as well as in a human T‑cell leukaemia model81.
Interestingly, several B7‑H1– mouse tumours start to
express B7‑H1 during growth in vivo. Injection of an
antibody specific for B7‑H1 increased T‑cell immunity

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APC TReg cell
IL-6
and IL-10
GM-CSF and IL-4
↑ B7-H4
Cell cycle
T cell
Figure 2 | B7‑H4+ antigen-presenting cells in the
tumour microenvironment. Nature B7‑H4+Reviews
antigen-presenting
| Immunology
cells (APCs), such as tumour-associated macrophages,
induce T‑cell cycle arrest. B7‑H4 expression can be induced
by interleukin-6 (IL‑6) and IL‑10, and is inhibited by the
dendritic-cell differentiation cytokines granulocyte/
macrophage colony-stimulating factor (GM-CSF) and IL‑4.
Regulatory T (TReg) cells can trigger IL‑6 and IL‑10
production by APCs, and in turn upregulate B7‑H4
expression by APCs. APCs that have been conditioned by
TReg cells inhibit T‑cell function through B7‑H4. High levels
of TReg cells, and IL‑6 and IL‑10 are found in the tumour
microenvironment, which helps to explain the observation
of B7‑H4+ APCs in this environment.
and induced tumour regression82. In these experimental
settings, it could not be excluded that B7‑H1 expression
by host cells, especially immune cells, could also have a
role. In this regard, PD‑1-deficient mice79,83 were shown
to have increased T‑cell immunity and were more resist-
ant to the outgrowth of transplanted murine tumours,
which indicates that host-derived B7‑H1 has a negative
effect on tumour immunity. In addition, recent studies
show that the expression of B7‑H1 could also func-
tion as a receptor to transmit an anti-apoptotic signal
to cancer cells as a means to resist immune-mediated
destruction27 (see later).
B7‑H1 expression by host cells. Myeloid DCs in human
tumours and tumour-draining lymph nodes express
high levels of B7‑H1 (Refs 23,45) . The interaction
between B7‑H1+ myeloid DCs and tumour‑associated
T cells leads to the downregulation of expression of
myeloid-DC-derived IL‑12 and upregulation of expres-
sion of the immunosuppressive cytokine IL‑10 by
myeloid DCs in a B7‑H1-dependent manner. Blockade
of B7‑H1 on tumour-infiltrating myeloid DCs increases
IFNγ production by T cells and promotes tumour infil-
tration by IFNγ-producing T cells. Adoptive transfer of
such T cells improves the clearance of human tumours
in xenotransplanted mice 23. These data support the
idea that B7‑H1 has a role in the downregulation of
DC‑mediated tumour immunity.
In the DA1-3b/C3H mouse model of acute myeloid leu-
kaemia, dormant tumour cells resist CTL‑mediated killing
owing to high levels of B7‑H1 expression by tumour cells84.
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In this model, the injection of irradiated acute myeloid
leukaemia cells transduced by CXC‑chemokine ligand
10 (CXCL10) led to prophylactic immunity in mice.
Interestingly, CXCL10 stimulated B7‑H1 expression by
NK cells, and NK‑cell-associated B7‑H1 was essential
for this prophylactic immunity38. These data indicate
that a stimulatory counter‑receptor for B7‑H1 is
expressed by T cells in the dormant tumour state owing
to the unique tumour microenvironment. It remains to
be determined if this mechanism is operative in other
tumour models and in patients with cancer.
B7‑H4. Although high levels of B7‑H4 expression
are observed in human cancers (TABLE 2), there are no
published data showing that the expression of B7‑H4
by cancer cells can lead to accelerated tumour growth
or progression in immune-competent animals. The
immunopathological relevance of B7‑H4 has only
been studied in patients with ovarian cancer. High
levels of B7‑H4 expression are found on a popula-
tion of tumour-associated macrophages in patients
with ovarian carcinoma. B7‑H4+ macrophages inhibit
TAA-specific T‑cell effector function31. These findings
show that B7‑H4 is a negative regulator of TAA-specific
T‑cell immunity and is a molecular target for tumour
immunotherapy.
In summary, B7‑H1 and B7‑H4 are selectively
expressed by various cellular components in the tumour
microenvironment, where they can inhibit tumour-
specific T‑cell immunity.
Cancer progression
Clinical data have documented that the expression of
inhibitory B7 molecules correlates with poor prog-
nosis of various types of human cancer (TABLES 1,2).
However, all of these studies are retrospective and can-
cer tissues were evaluated for the expression of these
molecules at a specific time point. As it is unknown
whether the level of expression of inhibitory B7 mol-
ecules varies during disease progression, the conclu-
sions and the implications from these analyses should
be carefully considered. Nevertheless, these studies
represent an important step towards understanding
the prognosis of and developing novel treatments for
patients with cancer.
High levels of expression of B7‑H1 were initially
reported in many human tumours44. Subsequent stud-
ies confirmed and extended these observations (TABLE 1).
Frozen47 and formalin-fixed85 tumour tissues of clear-cell
renal carcinoma stained with a human B7‑H1-specific
monoclonal antibody44 showed that B7‑H1 expression
is an indicator of poor prognosis for patient survival47.
In this study, however, the expression of B7‑H1 by
tumour-infiltrating lymphocytes derived from a frac-
tion of patients was also significantly associated with
poor prognosis47. Some reports have shown that B7‑H1
expression on tumour cells might also be associated with
decreased numbers of tumour-infiltrating lymphocytes
in patients with cancer86,87. Similarly, B7‑H1 expression
was also identified as a poor prognostic factor in patients
with oesophageal, gastric88,89 and ovarian87 cancers.
REVIEWS
Anergy
A state of non-responsiveness
to antigen. Anergic T or B cells
cannot respond to their
cognate antigens under
optimal conditions of
stimulation.
Exhaustion
An ‘operational’ definition that
refers to the loss of antigen-
specific T‑cell responses in vivo
after prolonged or repetitive
stimulation with antigen. This
has been best observed in a
model of infection with
lymphocytic choriomeningitis
virus Docile strain, for which
the exact mechanism is still not
understood.
472 | june 2008 | volume 8 www.nature.com/reviews/immunol
The broad expression pattern of B7‑H1 in cancer
microenvironments and its relationship with clinical and
pathological parameters in patients with cancer provide
strong evidence that B7‑H1 is pathologically relevant,
and that B7‑H1 and its signalling pathway are justified
targets for treating human cancer.
Although the role of B7‑H4 expression by tumour
cells in evading tumour immunity has not been well
established, several human studies indicate that B7‑H4
expression might be associated with the progression of
certain types of human cancer. In patients with renal
carcinoma56 and prostate cancer90, B7‑H4 expression by
tumour cells is associated with adverse clinical features.
A recent study in patients with ovarian cancer showed
that the level of B7‑H4 expression by tumour-associated
macrophages, but not tumour cells, correlates with the
number of TReg cells in the tumour. Further, expression
of B7‑H4 by macrophages and the number of TReg cells
are both negatively associated with patient outcome55. In
this context, B7‑H4 is shown to be a signature gene that
is consistently expressed in breast cancer91.
Mechanisms of action
B7‑H1-expressing cells use at least six distinct mecha-
nisms to evade T‑cell immunity (FIG. 3): inducing apop-
tosis, anergy or exhaustion of T cells, forming a molecular
shield to protect tumour cells from lysis, inducing pro-
duction of the immunosuppressive cytokine IL‑10 and
promoting TReg-cell-mediated suppression. It is possible
that these mechanisms work as a hierarchy to evade
immunity at different levels of T‑cell function to impose
tight control.
Apoptosis. Co-culture with B7‑H1+ tumour-cell lines
increased the apoptosis of human TAA-specific T cells;
blocking B7‑H1 decreased this apoptosis44. Subsequent
studies showed that B7‑H1-mediated apoptosis is a
common physiological process used by the host to
maintain homeostasis in peripheral tissues. For example,
B7‑H1-deficient mice have an accumulation of CD8+
T cells in the liver due to decreased apoptosis75. Liver
Kupffer cells92 and stellate cells93 constitutively express
B7‑H1, and human hepatocytes express low levels
of B7‑H1 (Ref. 60). This ready availability of B7‑H1 in
the liver might explain the decreased apoptosis of T cells
in B7‑H1-deficient mice75. B7‑H1 is also constitutively
expressed in the eye. After corneal allografting, B7‑H1+
corneal endothelium interacted with PD‑1+CD4+ T cells
and led to T‑cell apoptosis43. This observation could at
least partially explain how the immune-privileged status
of the cornea could be established.
B7‑H1 could have a role in the induction of effec-
tor T‑cell apoptosis in both a PD‑1-dependent and
-independent manner. In one human T‑cell clone, B7‑H1
can induce apoptosis of PD‑1– T cells44, but in most mouse
models, PD‑1 is required for B7‑H1‑mediated apoptosis17.
However, B7‑H1 can bind to PD‑1 (Ref. 21) and CD80
(Ref. 25), and thereby regulate T‑cell function. The detailed
molecular mechanisms of apoptosis mediated by B7‑H1
remain to be elucidated, and could occur indirectly or
through an uncharacterized direct pathway.
© 2008 Nature Publishing Group
Anergy. The role of B7‑H1 in T‑cell anergy was deter-
mined with the use of a cell-culture system in which
alloreactive T cells were induced by monocyte-derived
DCs. IL‑10-treated DCs induced unresponsive T cells
similar to anergic T cells, but these T cells could be
rescued by restimulation with DCs treated with an
antibody specific for human B7‑H1 (Ref. 94). A subse-
quent study showed that resting DC‑induced tolerance
of CD8 + T cells in mixed bone-marrow chimaeras
could be prevented by the ablation of PD‑1+ T cells95.
In the non-obese diabetic (NOD) mouse model, B7‑H1
and PD‑1, but not CTLA4 and TReg cells, were shown
to be crucial for T‑cell tolerance and anergy96. Given
the inducible nature of B7‑H1 expression in peripheral
tissues and of PD‑1 expression by activated T cells, it
was assumed that effector T cells, after priming in the
lymph nodes, migrate to peripheral tissues, where they
are induced to express PD‑1, and become functionally
anergic when engaged with B7‑H1 on peripheral organs
through PD‑1. However, this view was challenged by
two recent studies97,98. These studies have shown that the
expression of PD‑1 can be induced on T cells while they
are still in lymphoid organs during priming. Blockade of
B7‑H1 or PD‑1 by neutralizing monoclonal antibodies
before T-cell egress to peripheral organs could convert
anergic T cells into fully activated effector T cells97,98.
Therefore, the interaction of B7‑H1 with PD‑1 could
regulate T‑cell anergy in both priming and effector
phases of an immune response. In the context of tumour
immune pathology, human tumour-associated DCs
highly express B7‑H1 (Refs 23,45) and PD‑1+ T cells99
are found in the tumours. It remains unknown whether
the B7‑H1–PD‑1 interaction induces anergy of human
TAA-specific naive and effector T cells.
Exhaustion. This mechanism was revealed in stud-
ies of chronic infection. PD‑1 is highly expressed by
functionally exhausted antigen-specific T cells, and
B7‑H1 could be detected in infected tissues and lym-
phoid organs. Blockade of B7‑H1 or PD‑1 can rescue
the functionality of these exhausted T cells100–103. The
data indicate that PD‑1 might transmit an inhibitory
signal that dominates TCR signalling and decreases
T‑cell responses during prolonged exposure to antigens
during chronic infection.
Cancer could be considered as a chronic inflam-
matory disease58. Not only do up to 15% of cancers
worldwide have a direct infectious origin104, but many
human tumours are also related to chronic irritation and
inflammation1. Human tumour-associated DCs highly
express B7‑H1, and blocking B7‑H1 markedly increases
the effector function of tumour T cells23. In this context,
a recent study showed that PD‑1 is upregulated on a sig-
nificant fraction of tumour-infiltrating T cells in patients
with melanoma and that blockade of PD‑1 increased
TAA-specific T‑cell proliferation and function99. Taken
together, these data indicate that B7‑H1 and PD‑1 could
result in human tumour-specific T‑cell exhaustion. This
notion, although it has not been formally tested in can-
cer, needs to be taken into consideration when designing
tumour immunotherapies.

IL-10 production
PD-1
Anergy
Exhaustion Apoptosis
Immune suppression
B7-H1
TReg cell
APC
B7-H1
Tumour cell
Molecular
shield
Protected from
cytotoxic lysis
CTL
Figure 3 | The inhibitory actions of B7‑H1 in tumour immune evasion. Tumour cells
and tumour-associated antigen-presenting cells (APCs) express high levels of B7‑H1. The
potential suppressive mechanisms of B7‑H1 have been addressed NatureinReviews
various| models
Immunology
in vitro and in vivo, and it is probable that a combination of mechanisms, rather than a
single mode of action, is used by B7‑H1-expressing cells. B7‑H1+ tumour cells and APCs
might induce T‑cell apoptosis, anergy, functional exhaustion or IL‑10 production. B7‑H1+
tumour cells might be resistant to lysis by cytotoxic T lymphocytes (CTLs); this has been
described as a molecular shield. Tumour-associated regulatory T (TReg) cells might express
B7‑H1 and mediate T‑cell suppression partially through the B7‑H1–PD‑1 pathway. The
detailed molecular mechanisms remain poorly understood.
Molecular shield. The inclusion of neutralizing mono-
clonal antibodies specific for B7‑H1 or PD‑1 often
increases TAA-specific CTL-mediated lysis or cytokine
release against murine and human tumour cells that
express B7‑H1 (Refs 82–84,105,106). This observa-
tion indicates that endogenous levels of expression of
B7‑H1 might be sufficient to confer resistance against
CTL‑mediated lysis. The effect of neutralizing monoclonal
antibodies specific for B7‑H1 or PD‑1 varies depend-
ing on the system, ranging from moderate to dramatic.
For example, after transfection to express high levels of
B7‑H1, P815 mouse tumour cells are much more resist-
ant to lysis by antigen-specific CD8+ T cells82. Similarly,
the addition of a B7‑H1-specific monoclonal antibody to
B7‑H1‑transfected B16‑F10 melanoma cells results in the
increased secretion of cytokines from 2C CTLs105. This
resistance to cytotoxic lysis mediated by the expression of
high levels of B7‑H1 depends on the B7‑H1–PD‑1 inter-
action and was described as being a ‘molecular shield’82.
In addition, tumour-specific T cells are more effective at
lysing human glioma cells that express wild-type PTEN
with low-level B7‑H1 expression than those that express
mutant PTEN with high-level B7‑H1 expression37. The
nature reviews | immunology volume 8 | june 2008 | 473
© 2008 Nature Publishing Group
REVIEWS
acquisition of lysis resistance by tumour cells occurs
rapidly, within 4–16 hours, and was also observed for
allogeneic27,105 and re-directed T cells37 in addition to TAA-
specific T cells. This effect could be interpreted in terms
of the rapid induction of suppressive effects on T cells
through interaction with PD‑1. However, further stud-
ies showed that this was due to the unique nature of the
tumour-cell surface, but not to the dysfunction of T cells,
because wild-type tumour cells in the presence of B7‑H1+
tumour cells in the same culture could still be lysed by
T cells82. By disabling the intracellular domain of B7‑H1
on cancer cells, the ‘molecular shield’ is eliminated and
the tumour cells become susceptible in vitro to immune‑
mediated destruction. Importantly, tumours expressing
B7‑H1 with a truncated intracellular domain also become
more susceptible to T‑cell-mediated immunotherapy
in vivo compared with tumours expressing wild-type
B7‑H1. By contrast, the intracellular truncation of PD‑1
on T cells does not eliminate the ‘molecular-shield’ effect27.
In addition, B7‑H1 reverse signalling in cancer cells also
renders resistance to apoptosis mediated by antibodies
specific for CD95 (also known as FAS) and by staurosporin
toxin from Streptomyces staurospores (a broad-spectrum
protein-kinase inhibitor)27. In light of its broad expres-
sion pattern, B7‑H1 might be a ubiquitous anti-apoptotic
receptor expressed by cancer cells and might have a
general role in the resistance of tumour cells to immune
destruction and other apoptosis-based therapies.
IL‑10 production. Selective induction of IL‑10 was found
initially following the stimulation of human T cells with
CD3-specific antibody and B7‑H1–immuno­globulin
fusion protein20. Tumour-associated B7‑H1+ DCs also
induce T‑cell production of IL‑10 (Ref. 23). Subsequent
studies have established a correlation between the upreg-
ulation of B7‑H1 expression and increased levels of IL‑10
in patients with HIV and HBV infection107,108. It remains
to be determined whether increased IL‑10 production
has an important role in B7‑H1-mediated suppression
of T‑cell responses in vivo.
TReg-cell-mediated suppression. It has been suggested that
B7‑H1 is involved in the development and function of
TReg cells. B7‑H1+ vascular endothelial cells109 and gastric
epithelial cells110 induce the development of TReg cells in
an in vitro culture system. However, it has not been shown
that B7‑H1 or PD‑1 is required for TReg-cell differentia-
tion in vivo. In tumour-bearing mice, TReg cells activated
by IDO+ DCs induce B7‑H1 expression on target DCs.
Importantly, the ability of these TReg cells to suppress
T‑cell activation could be abrogated by antibody specific
for B7‑H1 (Ref. 111). In support of this observation, it has
been shown that human tumour-associated DCs express
B7‑H1 and mediate T‑cell suppression in a B7‑H1-
dependent manner23,45. By contrast, in non-Hodgkin lym-
phoma, intratumoral CD4+CD25+ TReg cells can express
B7‑H1, and blocking B7‑H1 with a monoclonal antibody
partially decreases TReg-cell-mediated T‑cell inhibition112.
These results indicate that B7‑H1 expression by tumour-
associated DCs and TReg cells might contribute to tumour
immune suppression.
REVIEWS
Small interfering RNA
Double-stranded RNAs
(dsRNAs) with sequences that
precisely match a given gene
are able to ‘knock down’ the
expression of that gene by
directing RNA-degrading
enzymes to destroy the
encoded mRNA transcript. The
two most common forms of
dsRNAs used for gene silencing
are short — usually 21-bp long
— small interfering RNAs
(siRNAs) or the plasmid-
delivered short hairpin RNAs
(shRNAs).
Antisense oligonucleotides
Short, gene-specific sequences
of nucleic acids that are
of the opposite strand
(complementary) to the
targeted mRNA. Classical
antisense oligonucleotides
target specific strands of RNA
within a cell, thereby
preventing translation of these
RNAs.
474 | june 2008 | volume 8 www.nature.com/reviews/immunol
B7‑H4 can also evade tumour immunity. B7‑H4 has
been studied in less detail than B7‑H1 in the context of
tumour immune evasion, but there is evidence indicat-
ing that B7‑H4 might exert its function through myeloid
APCs and TReg cells to mediate T‑cell suppression in the
tumour microenvironment31,55,74. Tumour‑associated
macrophages markedly outnumber other types of APC,
such as DCs, and form an abundant population of APCs in
solid tumours113–116. One population of ovarian‑cancer-
associated macrophages expresses high levels of B7‑H4,
and these B7‑H4+ macrophages induce T‑cell cycle arrest
in vitro and in vivo partially through B7‑H4 (Ref. 31).
These findings indicate that B7‑H4 might contribute to
tumour immune evasion, and that B7‑H4 is a molecular
target for tumour immunotherapy.
In human ovarian cancer, TReg cells and B7‑H4+
macrophages are co-localized and their numbers are
correlated in the tumour environment16,31,55,74. TReg cells
trigger high levels of IL‑6 and IL‑10 production by APCs,
and in turn, these cytokines stimulate the expression
of B7‑H4 by APCs, which renders the APCs immuno­
suppressive55 (FIG. 2). These findings are in line with the
observations that macrophages spontaneously produce
IL‑6 and IL‑10 in the ovarian tumour environment55,62.
These data mechanistically link IL‑10, B7‑H4, TReg cells
and APCs, and provide a new cellular and molecular
mechanism for TReg-cell-mediated immunosuppression
at the level of APCs13,55 (FIG. 2).
Implications for cancer immunotherapy
Many tumour-associated APCs and tumour cells express
B7‑H1 and B7‑H4, and these molecules can mediate
T‑cell suppression. The manipulation of B7-induced
immune suppression might therefore be a broadly appli-
cable therapeutic modality to treat human cancers.
B7‑H1 and PD‑1 blockade. Preclinical data have set the
stage for clinical trials by blocking B7‑H1 in patients with
cancer. In the context of its suppressive effects on T cells
and anti-apoptotic effect on tumour cells, it would seem
beneficial to block B7‑H1 using neutralizing antibodies.
However, antibodies specific for B7‑H1 could potentially
also block the interaction of B7‑H1 with a putative co-
stimulatory receptor. In this regard, it has been reported
that local expression of B7‑H1 can provide positive co-
stimulation for naive T cells and promote organ-specific
autoimmunity and transplant rejection in mice117. For
obvious reasons, therapeutic antibodies should be tested
for their ability to block the B7‑H1–CD80 interaction in
addition to blocking B7‑H1–PD‑1 binding. Despite the
possible immune-stimulatory roles of B7‑H1 in some
mouse models of transplantation and autoimmune
diseases, the effects of B7‑H1 are largely immunosup-
pressive on mouse and human tumour immunity. In
terms of the suppressive effects of B7‑H1, blocking
B7‑H1 could possibly enhance ongoing autoimmune
diseases. For example, treatment with B7‑H1-specific
antibody moderately accelerates experimental autoim-
mune encephalomyelitis in mice118. B7‑H1-deficient
NOD mice also develop diabetes more rapidly than wild-
type NOD mice119, and the loss of B7‑H1 expression on
© 2008 Nature Publishing Group
non-haematopoietic cells is crucial for the accelerated
disease120. However, in light of the mild autoimmune
phenotypes in B7‑H1-deficient mice75,76, B7‑H1 block-
ade will be unlikely to result in the generation of severe
autoimmune disease.
In addition to the effects of B7‑H1 on transplantation,
autoimmune diseases and tumours, it has been found
that trophoblasts, which are located in the maternal–
fetal interface, express B7‑H1, and B7‑H1+ trophoblasts
might have a role in the suppression of maternal–fetal
immunity42. Therefore, a potential side effect of B7‑H1
blockade by antibody in pregnant women could be the
termination of pregnancy. Nevertheless, B7‑H1-deficient
mice produce normal size litters, which indicates that
this is also a less likely event.
Similarly, neutralizing antibodies specific for PD‑1
will be an important addition to clinical trials. However,
neutralizing antibodies specific for PD‑1 might block the
interaction of PD‑1 with B7-DC (FIG. 1), another counter-
receptor for PD‑1 with potentially stimulatory effects. In
addition, PD‑1-specific antibodies might increase the
risk of severe autoimmune diseases, as predicted from
the spontaneous development of autoimmune diseases
in PD‑1-deficient mice17,18. Finally, although in vitro
assays support the claim that certain specific monoclonal
antibodies are antagonistic, if appropriate crosslinking is
provided, these antibodies could be potentially agonis-
tic121. Nonetheless, the significant potential benefits of
the clinical application of B7‑H1–PD‑1 blockade warrant
extensive experimental and clinical studies in patients
with cancer.
B7‑H4 blockade. Efficient neutralizing antibodies specific
for human B7‑H4 are not yet available. Small interfering RNA
(siRNA)54 and antisense oligonucleotides specific for B7‑H4
(Refs 31,74) have been used to block B7‑H4 expression.
Blocking the expression of B7‑H4 by tumour‑associated
macrophages disables their suppressive capacity, enables
TAA-specific effector T‑cell function and reduces tumour
growth in human ovarian cancer xenografts31,74. Taken
together with the proposed inhibitory role for B7‑H4 in
mouse systems28–30, these data justify B7‑H4 as a promis-
ing new target for development of therapeutic reagents for
the treatment of human cancers.
Combinatorial blockade. It is probable that multiple
suppressive mechanisms mediate immune evasion in a
given tumour. Combinatorial treatments will therefore
be required to reverse tumour immune-escape pathways
and lead to potent TAA-specific T‑cell immunity. In
tumour-bearing mouse models, for example, blocking
B7‑H1 in combination with blocking TGFβ signalling
using neutralizing antibodies synergistically induces
tumour regression133. B7‑H1 expression is induced
on tumour-associated TReg cells in non-Hodgkin lym-
phoma and on target DCs in murine tumour‑draining
lymph nodes. These TReg cells inhibit the function of
PD‑1+ tumour-infiltrating T cells, partially through the
B7‑H1–PD‑1 pathway111,112. These studies indicate that
simultaneously blocking B7‑H1–PD‑1 and TReg cells
might be therapeutically relevant.
 REVIEWS

The administration of a blocking monoclonal anti-
body specific for B7‑H1 increases the therapeutic effects
of a co-stimulatory CD137-specific agonistic monoclonal
antibody82,122 and of tumour-cell vaccination123. B7‑H1
and PD‑1 blockade together with an HSP70 vaccine124
can increase T‑cell immunity and decrease tumour
growth and metastasis in mouse models. In addition to
these examples, blocking the B7‑H1–PD‑1 pathway in
combination with blockade of other well-defined sup-
pressive molecules, including CTLA4, VEGF, B7‑H4,
TGFβ, arginase or IDO1, could be possible options in
preclinical and clinical settings to treat cancer.
Concluding remarks
There is now compelling evidence to show that tumours
escape host immunity by actively developing multiple
suppressive mechanisms in the tumour microenviron-
ment. The mechanisms that underlie the interactions
between the immune system and the tumour micro-
environment, particularly in humans, are a crucial and
understudied area of cancer immunology, the under-
standing of which will have a significant impact on
the success of immunotherapy strategies. The selective
expression of inhibitory B7 molecules in the tumour
microenvironment has been determined as an impor-
tant immunosuppressive mechanism in many types
of human tumour. Therefore, the manipulation of the
expression of and signalling through these molecules is
an attractive strategy to treat human cancers. However,
as we move forward to clinical trials, we have to bear in
mind several possibilities. First, the immune suppres-
sion mediated by inhibitory B7 molecules might not be
the only or the main immunosuppressive mechanism
used by certain tumour stages and/or certain types of
tumour. Therefore, it is essential to define the nature and
functional relevance of inhibitory B7-family members
in each individual human tumour microenvironment.
Second, the interactions between the B7-family mem-
bers and their receptors are complex and might reflect
differences in temporal and spatial expression of these
molecules and their affinities for one another in the
tumour microenvironment. Third, blocking inhibitory
B7 molecules might result in autoimmune diseases.
Finally, the receptor(s) and signalling pathways have not
been identified for several B7-family members. These
limitations will probably constrain the clinical applica-
tion of targeting inhibitory B7-family members as a
therapeutic modality. Identification of all the counter-
receptors in these pathways and careful analysis of their
positive and negative regulatory functions will help us to
design more elegant strategies to maximize anti‑tumour
immunity while decreasing the risk of autoimmune dis-
eases. In addition, targeting one pathway will be highly
unlikely to lead to reliable and consistent clinical effi-
cacy, and combinatorial therapeutic regimens will need
to be developed.

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Acknowledgements
We would like to thank our former and current trainees and
collaborators for their intellectual input and hard work. The
work described in this Review was supported by grants from
the United States National Institutes of Health and the United
States Department of Defense.
DATABASES
Entrez Gene: http://www.ncbi.nlm.nih.gov/entrez/query.
fcgi?db=gene
B7-DC | B7-H1 | B7-H2 | B7-H3 | B7-H4 | CD80 | CD86
FURTHER INFORMATION
Weiping Zou’s homepage:
http://sitemaker.umich.edu/zou.lab/home
Lieping Chen’s homepage:
http://gradimmunology.med.som.jhmi.edu
All links are active in the online pdf