Originally published online as doi:10.1189/jlb.0802416 on June 3, 2003
Published online before print June 3, 2003
(Journal of Leukocyte Biology. 2003;74:311-330.)
© 2003
by Society for Leukocyte Biology
Tracking death dealing by Fas and TRAIL in lymphatic neoplastic disorders: pathways, targets, and therapeutic tools
Richard Greil*,
,1,
Gabriele Anether*,
Karin Johrer and
Inge Tinhofer*,
* Department of Internal Medicine, Division of Hematology and Oncology, Laboratory of Molecular Cytology, University of Innsbruck Medical School, Austria; and
Tyrolean Cancer Research Institute, Innsbruck, Austria
1Correspondence: Laboratory of Molecular Cytology, Department of Internal Medicine, Division of Hematology and Oncology, Innsbruck University Hospital, Anichstrasse 35, A-6020 Innsbruck. E-mail: richard.greil{at}uibk.ac.at
ABSTRACT
In the past decade, it was concluded from a number of investigations
that death domain-containing members of the tumor necrosis factor-receptor
(TNF-R) family and their ligands such as Fas/FasL and TNF-related
apoptosis-inducing ligand (TRAIL)-R/TRAIL are essential for
maintaining an intact immune system for surveillance against
infection and cancer development and that nondeath domain-containing
members such as CD30 or CD40 are involved in the fine tuning
of this system during the selection process of the lymphatic
system. In line with this conclusion are the observations that
alterations in structure, function, and regulation of these
molecules contribute to autoimmunity and cancer development
of the lymphoid system. Besides controlling size and function
of the lymphoid cell pool, Fas/FasL and TRAIL-R/TRAIL regulate
myelopoiesis and the dendritic cell functions, and severe alterations
of these lineages during the outgrowth and expansion of the
lymphoid tumors have been reported. It is the aim of this review
to summarize what is currently known about the complex role
of these two death receptor/ligand systems in normal, disturbed,
and neoplastic hemato-/lymphopoiesis and to point out how such
knowledge can be used in developing novel, therapeutic options
and the problems that will have to be faced along the way.
Key Words: lymphoma • tumor counterattack • novel therapeutic strategies
INTRODUCTION
Extensive control over life and death of hematopoietic cells
is required to keep them in balance for the maintenance of tissue
homeostasis. This homeostasis needs specific adaptations to
actual demands such as selective expansion or narrowing of distinct
compartments of effector cells in the myeloid and lymphoid compartments.
This is achieved by close involvement of hematopoietic cells
in regulatory networks comprising the intimate cross-talk with
distinct bystander cells of the lymphoid and bone marrow (BM)
microenvironment and conversely, a modulation of responses to
cytokines promoting or inhibiting growth and survival. Death
domain-containing members of the tumor necrosis factor-receptor
(TNF-R) family such as Fas/FasL and TNF-related apoptosis-inducing
ligand (TRAIL)-R/TRAIL are essential tools for delivering lethal
stimuli to specific targets at distinct organs and thus contribute
to a fine-tuned system of cell type-specific apoptosis regulation.
In the lymphoid compartment, the main death-inducing molecules
are FasL, TRAIL, TNF-
, perforin, and granzyme. The pivotal role
of the Fas/FasL system in regulating normal B and T cell function
[
1
], suppression of autoimmunity [
2
], control of infection
[
3
], and immune surveillance [
4
] has been extensively analyzed.
As a result of its dual role, namely, in self-control of T cell
expansion and in killing of virally infected or neoplastically
transformed target cells, alterations of the Fas/FasL system
are at the interface among autoimmunity, immune evasion of cancer
cells, and immune deficiency, which are all well-known features
of neoplastic diseases, in particular, of the lympho-hematopoietic
system. TRAIL has been less-extensively investigated than FasL,
but its preferential cytotoxicity against neoplastic cells and
its low toxicity in normal tissues warrant further studies on
its function and therapeutic potential in cancer.
It is the aim of this review to focus on the role of Fas and TRAIL-R signaling in normal lymphopoiesis and their significance in the pathophysiology of lymphomas. In addition, current concepts regarding the therapeutic targeting of these two death receptors will be discussed.
STRUCTURE AND FUNCTION OF Fas DEATH RECEPTOR/LIGAND SYSTEM
A detailed description of the molecular structure of Fas (CD95,
APO-1) and its ligand and of Fas signaling is beyond the scope
of this review (see ref. [
5
]). Briefly, Fas is a member of
the TNF-R family involved in mediating death signals [
6
]. It
is a type I transmembrane receptor widely expressed in human
tissues for which alternate splicing variants may occur, giving
rise to soluble forms of Fas with unknown functions [
7
,
8
].
The induction of signaling usually requires binding of the specific
ligand with trimerization of the receptor. Recruitment of Fas-associated
death domain (FADD) and procaspase-8 leads to the formation
of an active death-inducing signaling complex (DISC), which
enables limited proteolytical cleavage of procaspase-8 and its
release into the cytoplasm. The activated caspase-8 directly
acts on downstream effector molecules such as caspase-3 (type
I cells; ref. [
9
]), which kills cells through the cleavage,
and destruction of multiple cellular target structures. Knockout
experiments in mice are detailed in
Table 1
. They support the
view that signaling along the Fas pathway does not interfere
with the function of Bcl-2 and BcL-X
L during normal lymphocyte
development [
23
]. However, in some neoplastic human cell types,
there exists an alternative pathway to Fas-induced cell death.
In case of insufficient recruitment of caspase-8, cleavage of
Bid occurs, leading to the breakdown of mitochondrial membrane
potential and release of proapoptotic members of the apoptosome-like
cytochrome C and procaspase-9, which after binding to apoptosis
activating factor-1 (APAF-1), converge on the common effector
caspase-3 (type II cells; ref. [
9
]). Specific molecules such
as IAP-1 and -2, XIAP, and survivin, all of which bind to and
inactivate initiator caspase-9 and/or effector caspases (i.e.,
3 and 7; reviewed in refs. [
24
,
25
]), also control the activity
of caspases. Not surprisingly, within a signaling system with
the capability to irreversibly prime a cell to death, IAPs in
turn are under the control of proteins such as SMAC/DIABLO,
which are stored in mitochondria and released together with
cytochrome C or APAF-1. SMAC/DIABLO protein binds IAPs [
26
]
and XIAP [
27
], thereby releasing them from the caspase, which
then becomes active. Thus, death receptor signaling is controlled
at many levels and characterized by a substantial degree of
redundancy and pleiotropism, which is caused by the capability
of cross-talk between type I and type II signaling pathways;
by an amplification loop, whereby downstream caspases such as
caspase-3 activate caspase-8 [
28
] or caspase-9 [
29
]; and by
a large number of agonists and antagonists acting at a particular
level of signaling. This is evidenced by the fact that knockout
models of several molecules within these signaling cascades
have no apparent phenotype or display no significant alteration
of sensitivity to cytotoxic mechanisms
(Table 1)
. However,
deletions at critical interfaces of type I and II signaling
pathways such as FADD mutations and/or caspase-3 may be deleterious
for embryonic or early postnatal development
(Table 1)
and
may be involved in escape from immune control and tumor development
of certain B and T cells (see below). In addition, the differences
in organ-specific equipment with signaling components and their
alterations may contribute to alteration of Fas sensitivity
in specific lymphoma types, an aspect that has to be considered
in novel therapeutic approaches.
The FasL represents a type II TNF-related transmembrane molecule
[
5
], and under physiological conditions, its expression is
confined to a limited spectrum of cell types, in particular
to activated T cells [
30
]. Membrane-bound FasL may be released
after packaging into microvesicles [
31
] or after cleavage of
its extracellular domain by metalloproteinases [
32
]. The biological
functions of murine and human sFasL are different, as are the
functions of human sFasL in different situations. Although the
direction of signal transduction is usually from ligand to receptor,
reverse signaling via the FasL has been implicated in T cell
functions [
33
]. In rare situations, Fas/FasL effects other
than the induction of apoptosis have been reported [
34
]. The
regulation of Fas and FasL expression as well as of Fas sensitivity
is under the influence of a complex network of cytokines (reviewed
by R. Greil et al., submitted for publication).
In conclusion, the specific composition of the humoral micromilieu and/or the triggering of specific membrane receptors by components of the cellular microenvironment modify a relationship between FasL+ effector and Fas+ target cells. These interactions are operative in normal and neoplastic hematopoiesis. However, in the latter, the oncogenetic transformation process may functionally alter molecules representing physiological and essential constitutents of an intact Fas signaling pathway and thus induce intrinsic resistance to Fas.
CONSTITUTION AND EXPRESSION OF TRAIL AND ITS RECEPTORS
TRAIL or Apo-2L is a type II membrane protein (reviewed in ref.
[
35
]), which exerts maximal biologic activity in a trimeric
form [
36
]. TRAIL is unique among the family of death receptor
ligands because of two characteristics still poorly understood:
In contrast to FasL, TRAIL mRNA expression is observed in a
broad spectrum of tissues ranging from peripheral blood lymphocytes,
spleen, and thymocytes to many solid organs but is absent in
brain, liver, and testis [
36
]; and TRAIL does not harm most
of the normal tissues [
37
,
38
] but is lethal in a wide range,
i.e., 60% of the tested neoplastic cell lines, of many types
of native human tumor cells (
Table 2
). In a quest for specific
regulators of sensitivity to TRAIL, a broad family of receptors
has been detected. TRAIL-R1 [
39
] and TRAIL-R2 [
37
] are type
I transmembrane proteins exerting proapoptotic signals. The
two killer receptors demonstrated a broad and partly overlapping
pattern of expression, suggesting that they may serve as an
alternate or "backup" system, allowing the immune system to
control aberrant cells even if one of the receptors had failed.
This seemed to be supported by initial experiments, which pointed
to a differential role of adaptor molecules in linking the two
TRAIL receptors to distinct signaling pathways [
39
]. However,
more recent experiments found both receptors to associate with
FADD and procaspase-8 in several cell lines [
40
]. These data
were confirmed by murine knockout experiments [
41
], demonstrating
that TRAIL-R1 and -R2 use signal-transduction pathways very
similar to that of the Fas system [
42
,
43
].
TRAIL-R3/TRID/DcR1 [
37
] lacks a cytpoplasmic domain and after
ligation, does not induce apoptosis. Its function as a decoy
receptor is weak and transient [
44
], speaking against its universal
function. TRAIL-R4 activates the antiapoptotic nuclear factor
(NF)-
B pathway but is unable to transduce proapoptotic signals,
as it lacks a part of the cytoplasmic death domain [
44
] (reviewed
in ref. [
35
]). Finally, TRAIL may bind to osteoprotegerin [
45
],
a soluble TNF-R homologue that inhibits osteoclastogenesis by
binding to the osteoprotegerin ligand. As a result, bone density
increases in vivo [
45
]. By this interaction, osteoprotegerin
inhibits TRAIL-induced cell death in the lymphatic cell system
and enables TRAIL to interfere with bone formation [
45
].
Early investigations explained the different sensitivity of normal versus neoplastic cells and the differential sensitivity of various tumor types to TRAIL signaling by the various patterns of expression of full-length versus decoy receptors with or without activation of the antiapoptotic NF-B pathway [40
]. The critical review of data mentioned above and presented in Table 2
sheds some doubt on such a simplified view for the following reasons: There is a broad overlap in expression profiles of pro- and antiapoptotic receptors (see Table 2
), and the correlation between their expression levels and sensitivity of cells to TRAIL is weak in normal dendritic cells (DCs) [54
], tumor cell lines [35
], and many native human tumor cells (Table 2) . Rather, receptor/DISC composition, equipment with caspases and their inhibitors, as well as external influences of the microenvironment cooperate in regulating TRAIL sensitivity in the various tissues.
REGULATION OF NORMAL LYMPHOPOIESIS BY DEATH RECEPTOR SYSTEMS
Apoptosis is a central mechanism for tuning the immune system,
controlling the expansion of inappropriately selected T cells,
or downsizing the superfluous cells of a specific T cell response,
thus preventing permanent damage to, e.g., virally infected
tissues. Less than 3% of T cells survive the selection process
within the thymus, and the vast majority of thymocytes die by
apoptosis, thereby inhibiting the expansion of autoreactive
T cells. Initially, it was believed that the Fas pathway was
not involved in the negative-selection process of thymocytes,
as the T cell receptor (TCR) repertoire of
lpr and
gld mice
with their mutations in Fas and FasL genes, respectively, was
not altered (reviewed in ref. [
55
]), and thymocytes at various
maturation stages survive Fas ligation as a result of their
unique expression of a membrane-bound decoy receptor [
56
].
However, where T cells face high antigen concentrations [
57
]
and in certain TCR transgenic mouse models [
58
], Fas might
play a role in the negative-selection process of thymocytes.
Peripheral T cells up-regulate FasL after antigen contact and
under the influence of IL-2, are capable of killing target cells
while resisting Fas-induced apoptosis. Finally, the immune response
is terminated by up-regulation of Fas and among other processes,
down-regulation of FLIP and Bcl-2, driving T cells to suicide
or fratricide (AICD; ref. [
59
]). Results from subsequent analyses
suggest that this regulatory circuit has to be more complex:
In the course of antigenic stimulation, a reverse, costimulatory
signal is provided by FasL, thereby increasing the proliferative
capacity of CD4
+ and CD8
+ T cells [
33
,
60
]. Not only FasL
but also Fas are able to trigger death and activation signals.
Such a conclusion has been drawn from studies demonstrating
the induction of proliferation in T cells when they were cultured
with agonistic anti-Fas monoclonal antibodies (mAb) together
with anti-CD3 mAb [
61
]. More indirect evidence supporting the
view of Fas being involved in T cell activation has been provided
by analyses of T cells in FADD-deficient mice [
15
]. Using this
genetic approach, deficiencies in the development of immature
and the proliferation of mature T cells were observed [
15
].
In contrast to the Fas system, upon activation, thymocytes up-regulate TRAIL and TRAIL-R1 and -R2, thus sensitizing thymocytes to TRAIL. Although suggestive of a contribution of the TRAIL system to antigen selection of thymocytes, this could not be proved, leaving open the physiological role of TRAIL circuits in the thymus. TRAIL is also expressed on activated but not resting murine CD4+ and CD8+ T cells [62
], but the specific receptor is not increased, which enables peripheral T cells to resist autocrine suicide via TRAIL under conditions of activation [63
]. Although FasL-bearing T cells are also involved in the control of the immune system stimulated for expansion during inappropriate antigen selection, the central physiological targets for FasL- and TRAIL-bearing effector cells are virally infected and cancer cells.
B cell development
The Fas/FasL system is a central player in the negative-selection process of normal B cells, inducing antigen-specific B cell responses and inhibiting clonal expansion of autoreactive cells. lpr and gld mice are characterized by expanded B cells, increased pool of abnormal T cells, lymphadenopathy, splenomegaly, and production of double-stranded DNA antibodies [2
]. Fas plays an important role in the antibody-selection process during germinal center passage of B cells. Within this specific environment, preformed oligomeric, Fas-associated DISC complexes are expressed in B cells, but the interruption of the death pathway by their association with the inhibitory FLIP molecule rescues germinal center B cells from their rapid demise [64
]. Outside the germinal center, FLIP rapidly dissociates from the preformed DISC and allows death to occur, unless its continuous association is triggered by two different stimuli, namely ligation of the B cell receptor and contact with CD40L+ T cells or contact with follicular DCs (reviewed in ref. [65
]). The rapidity of the Fas/FLIP interaction therefore seems to serve as an emergency switch for apoptosis during the selection process. It prevents the survival of low-affinity B or plasma cells but in case of Fas resistance, allows prolonged recruitment of germinal center cells into the B cell memory pool [66
]. Although up-regulation of Bcl-2 or BcL-XL also confers resistance to Fas signaling in B cells, their expression after CD40L binding takes longer, suggesting that they play a role during memory or plasma cell differentiation rather than during the antigen-selection process.
After their maturation to plasma cells, B cells may still be partly under the control of the Fas/FasL system, as at least in B-CLL, hypogammaglobulinemia results from binding of tumor-associated mFasL to Fas-sensitive plasma cells [67
] (Fig. 1
). In contrast, within the mucosa-associated lymphoid tissue (MALT) of the gastrointestinal tract, plasma cells express FasL, pointing to their role not only as target but also as active effector cells of the immune system [74
]. The expression of TRAIL has been investigated in the murine system, where B220+ mouse B cells are intrinsically TRAIL+. The similar expression pattern of FasL and TRAIL in peripheral B and T cells points to a complementary effector function in the regulation of these cells.
Death receptor/death receptor ligand systems in the normal BM microenvironment
Although tumor-associated TRAIL [
75
] and to a lesser degree,
recombinant TRAIL interfere with erythropoiesis [
76
,
77
],
largely leaving other lineages of the hematopoietic cell system
unaffected [
53
,
78
], the Fas/FasL system is fundamentally
involved in the regulatory interplay between progenitor and
progeny in erythropoietic and granulopoietic cell lineages of
hematopoiesis [
79
] (for review, see R. Greil et al., submitted).
Given the close interdependence of this network with the cellular
and humoral composition of the surrounding microenvironment,
it is not surprising that even subtle alterations may cause
severe disturbances of the myelopoietic homeostasis, resulting
in a predisposition to the development of aplasia or leukemia
[
79
]. Neoplastic lymphocytes frequently expand within the BM,
secrete cytokines with the potential to alter Fas sensitivity
of hematopoietic cells, and although often resistant to Fas,
inadequately express death receptor ligands [
80
]. Some clinical
features of lymphatic neoplastic diseases, such as anemia in
aggressive myeloma [
68
,
75
] and immune deficiencies in B-CLL
[
67
,
69
]
(Fig. 1)
, may therefore be attributed to tumor-induced
alterations of the death receptor/ligand systems in the BM.
An understanding of the nature of these interactions and the
differences between Fas and TRAIL within this compartment are
essential for successfully targeting lymphatic tumors via modification
of this axis without additional risk to the patient.
THE ROLE OF DEATH RECEPTORS IN DC FUNCTION AND DEVELOPMENT
Death receptor ligands are also involved in the immunoregulatory
network at the interface between DCs and effector cells. They
may influence the physiological function of DCs, which express
Fas and TRAIL-R2 and -R3, at all maturation stages. Only immature
DCs succumb to TRAIL-mediated apoptosis, and mature DCs are
resistant, probably as a result of their higher levels of FLIP
[
54
]. The fact that mature DCs express TRAIL might allow them
to regulate the development of TRAIL-sensitive DC precursors
and up-regulate (via antigen presentation) or down-regulate
antigen-specific T cells (via TRAIL-mediated apoptosis) [
81
].
In fact, T cells might be suppressed via TRAIL under certain
physiological and pathological conditions. HIV-uninfected CD4
+ cells of AIDS patients are killed by TRAIL
+ CD4
+ cells in HIV-infected
lymphoid organs [
82
], and cytomegaly [
83
] and measle virus
[
84
] up-regulate TRAIL and FasL in DCs and kill activated T
cells, thus providing virus defense by eliminating host cells
for viral replication. This effector function of death receptor
ligand-bearing DCs may also be important in tumor control (see
below).
DEATH RECEPTOR/DEATH RECEPTOR LIGAND SYSTEMS IN LYMPHATIC NEOPLASIAS
Several lines of evidence suggest that mutations of Fas or functional
inactivation of the Fas signaling pathway are associated with
an increased tumor rate and that Fas might be considered a tumor-suppressor
gene. Furthermore, aberrant expression of FasL on tumor cells
may be involved in tumor development and progression.
B cell malignancies in Fas/FasL-deficient mice
Although fas-deficient mice usually show only background incidence for the development of B cell lymphomas, the prolonged observation of C3H-gld and BALB-gld mice revealed a 28% and 57% lymphoma rate, respectively [85
]. Transfection of FLIP, an inhibitor of caspase-8, into murine A 20 lymphoma cells and their subsequent injection into an immunocompetent-recipient mice strain led to the development of rapidly growing tumors resisting control and rejection via death receptor ligands of T cells [86
]. The consequences of an altered Fas signaling pathway are aggravated by further T cell deficiencies [87
]. These data established inhibitors of death-receptor signaling as tumor-progression factors.
Cancer incidence under Fas-deficient conditions in humans
Autoimmune lymphoproliferative syndromes (ALPS) are inherited human diseases with increased incidence of autoimmunity and neoplasias observed also in gld and lpr mice. The ALPS phenotype is associated with inherited mutations in the Fas (type Ia) or the FasL gene (type Ib) [88
]. In inbred lpr and gld mice, essentially the same disease results from homozygous, recessive mutations in the genes encoding Fas and Fas ligand, respectively. However, in ALPS type Ia, individuals are more often heterozygous for mutant Fas alleles. By an unknown mechanism, the Fas protein encoded by the mutant allele dominantly interferes with the function of the wild-type protein [89
], causing a severe defect in apoptosis [90
]. The localization of mutations/deletions within the death domain of the Fas gene varies widely (between nucleotide positions 915 and 1123) in the cases reported by Martin et al. [89
] and so does the clinical spectrum of the disease manifestation. Although lymphadenopathy and splenomegaly are rather constant features, the number of cell types binding autoantibodies and the severity of their destruction differ substantially [89
].
In ALPS type II, it is assumed that a similar, although more severe, clinical phenotype is caused by an undefined, inherited gene defect in the absence of mutations in Fas or FasL genes. Finally, ALPS type III is a more heterogeneous group, as yet without any defined genetic cause. An increased incidence in lymphoma development has been described in one family with inborn genomic fas mutations [91
] and ALPS [92
]. Delayed onset and manifestation of the neoplastic disease at a mean age of 28 years [93
] suggest a need for acquisition of further oncogenetic events particularly in B cells. A recent survey of families with ALPS revealed a significantly increased risk of Hodgkin’s (up to 51-fold) and Non-Hodgkin’s lymphoma (NHL; up to 14-fold) and a broad range of histological types of NHL including one case of T-NHL [93
]. In all patients, tumor cells retained the heterozygous fas mutations and demonstrated severe disturbances in Fas-mediated killing. Female patients without fas mutations but severe disturbances in Fas signaling and/or ceramide-induced T cell death (autoimmune lymphoproliferative disease or type III disease) displayed an increased incidence of (standardized incidence ratio=1.87) and mortality (standardized mortality ratio=2.75) from cancer, but there was no particular preponderance of lymphomas [94
].
The FasL counterattack hypothesis
Neoplastic T cell lymphomas are capable of expressing FasL and of killing tumor-specific, Fas-sensitive, cytotoxic T cells as a result of their lineage derivation [95
]. However, a broad range of tumor types acquire FasL expression [96
97
98
] and the ability to escape the immune system, not only by modification of Fas sensitivity but also by defeating sensitive immune-effector cells (Fig. 1)
. The Fas counterattack hypothesis has been challenged, mostly on technical grounds [99
]. Other reasons for dissatisfaction with the hypothesis are observations that transfection and overexpression of allogeneic or xenogeneic FasL in grafted pancreatic islets do not kill autoreative T cells in diabetic animals but rather attract granulocytes, which destroy the graft [100
], and that transfection of tumor cells with FasL can induce tumor regression by tumor cell suicide [101
] or by the induction of an inflammatory response mediated by granulocytes and monocytes [101
]. There is, however, an appreciable and growing body of evidence supporting the Fas counterattack hypothesis, particularly based on observations made in native human tumor material without genetic modifications of the system [4
, 80
].
THE ROLE OF TRAIL IN TUMOR CONTROL
Several lines of evidence point to a crucial role of TRAIL in
tumor cell control. In TRAIL-deficient mice, there was an increased
susceptibility to chemical carcinogenesis, enhanced spontaneous
and experimental tumor metastases [
102
,
103
]. Different effector
cell types might be involved in this protection: (i) TRAIL is
constitutively expressed only on certain activated NK cell subtypes,
particularly those residing in the liver, and essentially contributes
to the protection of liver from the metastatic potential of
RENCA cells [
104
]. Furthermore, IL-12 can induce TRAIL expression
on NK cells in lung, liver, and spleen via a strictly IFN-
-dependent
pathway, and this establishes protection against metastatic
infiltration [
104
]. (ii) DCs may be crucial for establishing
antitumor immunity. Surprisingly, DCs may not only serve as
antigen-presenting machinery but turn into effector cells with
killing capacity against papilloma virus-infected, preneoplastic
epithelial cells [
105
]. IFN-
or IFN-
stimulation of CD11c
+ blood DCs and IFN-ß activation of monocyte-derived
[
106
] or CD34
+ cell-derived [
107
] DCs lead to expression of
TRAIL and turn DCs into cytotoxic effector cells against tumor
cells [
106
,
107
]. The killing capacity of DCs via TRAIL is
absent in blood precursor (pre) DCs but is acquired by them
at the CD11-positive stage [
81
]. By killing tumor cells via
TRAIL, DCs may subsequently serve a second function by taking
up apoptotic bodies of tumor cells, processing, presenting them
to CD8
+ cytotoxic T cells, and thus, inducing a broader antitumor
immunity. (iii) Certain T cells might use TRAIL to kill tumor
cells. In fact, CD4
+CD8dim
+ T cells isolated from cutaneous
T cell lymphomas are cytotoxic against autologous tumor cells
via a TRAIL-dependent mechanism [
108
]. Also, certain CD4
+ cells
express TRAIL after stimulation with the immune modulator
-galactosylceramide
and thus become capable of killing acute myeloid leukemia (AML)
cells [
109
].
Inversely, disturbances in the TRAIL/TRAIL-R system may favor the expansion of the malignant clone: (i) Mutation of TRAIL-R1 and -R2 renders neoplastic B cells insensitive to TRAIL and occurs in 6.8% of 117 NHL investigated [110
]. (ii) Neoplastic cells may aberrantly acquire the capacity to produce osteoprotegerin [111
]. Whether this phenomenon interferes with the TRAIL-mediated control of tumor is not yet clear. (iii) Like FasL, neoplastic lymphatic cells may express TRAIL, allowing them to kill T cells and suppress the immune system [112
]. The counterattack hypothesis about TRAIL, however, is less well investigated than about FasL.
DEATH RECEPTOR SYSTEMS IN SPECIFIC LYMPHATIC NEOPLASIAS
Given the role of the Fas/FasL system for the regulation of
normal T cell survival, Fas mutations can be expected to contribute
to the development of T cell tumors. Surprisingly, there is
currently no convincing evidence for an increased T cell leukemia/lymphoma
rate in lpr/lpr or gld/gld mice. However, lpr/lpr mutant mice
develop T cell lymphomas once they acquire additional oncogenetic
events such as constitutive high expression of L-MYC [
113
],
thus pointing to a role of Fas in the multistep carcinogenesis
of T cell lymphomas and leukemias.
T-ALL
Despite expression of Fas in the majority of primary T-ALL cases, these tumor cells are constitutively resistant to Fas-induced apoptosis [114
]. This is in contrast with tumor cells of patients with adult T cell leukemia, which expressed Fas and died after Fas ligation [115
]. Mutations within Fas, detected in rare cases of both types of native T cell malignancies, may account for Fas resistance [115
, 116
].
Inactivation of the Fas signaling pathway may occur more often in T cell leukemias than alterations in the structure of Fas and may contribute to Fas resistance. A comparison of neoplastic lymphoblasts of pediatric patients with ALL at diagnosis and at the first relapse showed a down-regulation of Fas and caspase-3, as well as an up-regulation of Bcl-2 expression in the latter [117
]. Deregulation of the transaldolase 1 stem cell leukemia expression commonly occurs in T-ALL [118
] and when overexpressed, contributes to the development of T cell malignancies [119
] and to the inhibition of apoptosis induced by Fas or cytotoxic agents [120
].
Peripheral T/NK cell neoplasias
Peripheral nasal T/NK cell lymphomas coexpress Fas, FasL, and perforin/granzyme [121
]. This is in good correlation with the observation that in NK cell lymphoma, mFasL was constitutively expressed, and sFasL was shed, whereas NK cells of healthy volunteers expressed FasL only upon activation [122
]. As the nonneoplastic cells within these tumors were often Fas+, neoplastic cells might cause apoptosis and necrosis of normal tissue constituents considered typical of this disease. In fact, apoptotic cells typically surrounded the proliferating tumor cells [121
]. Increased levels of sFasL observed during active phases of the disease in NK cell lymphomas usually correlated with signs of liver damage, declined during successful radiotherapy, and recurred during relapses of disease [123
]. In CD3+ large, granular lymphocytic leukemias, tumor cells expressed Fas and FasL to a similar extent as normal, activated CD3+ cells [124
] but resisted Fas-induced cell death in most cases. Fas resistance was not a result of mutations but rather associated with a failure to respond to CD3 cross-linking and a more aggressive course of the disease. In cutaneous T cell lymphomas, Fas expression was observed in all of the favorable CD30+ cases but only in one-third of the tumor stages of Mycosis fungoides and in only 22% of CD30- cases [125
]. Down-regulation of Fas paralleled disease progression from plaques to tumor, and FasL was present on tumor cells in 82% of cases. These findings favor a role of membrane-bound or soluble FasL in tissue destruction and morbidity and point to a sequence of transformation in which a loss of Fas sensitivity and up-regulation of FasL occur on neoplastic T cells. Indeed, T cell lymphomas and syngeneic tumor-specific T cells may coexpress Fas and FasL, giving rise to a bidirectional interaction and killing in both cell types [95
]. Up-regulation of FasL and intrinsic protection of tumor cells against Fas signaling may therefore confer a survival advantage on tumor cells by enabling them to escape from and to defeat specific cytotoxic T cells.
B cell neoplasias
Numerous observations have implicated the Fas/FasL system in the regulation of B cell homeostasis in many ways. Immunohistochemical analyses of the normal B cell compartments demonstrate positivity of secondary germinal centres of lymph nodes for Fas [126
, 127
] and caspase-3 [128
] but no Bcl-2 expression [129
]. Thus, the physiological B cell-immune reaction should still be under the control of Fas. An intact Fas signaling pathway may therefore be considered as tumor-suppressive.
MECHANISMS OF Fas RESISTANCE IN SPECIFIC B CELL NEOPLASIAS
Unimodal Fas expression has been shown to be a rather constant
feature of various histological subtypes of NHL, although the
staining intensity of Fas varied considerably [
126
,
130
] (for
details, see
Table 3
). These findings are consistent with the
Fas-staining patterns in normal B cell compartments in which
follicles are strongly positive, particularly within the centroblastic
cell fraction. However, independent of the level of Fas expression,
B cell lymphoma cells were intrinsically resistant to cross-linking
of the receptor [
130
]. Although Fas could be up-regulated on
normal and malignant B cells by CD40 and IL-4 costimulation,
this maneuver was only able to restore or increase Fas sensitivity
in the normal, not in the malignant cells. These results could
not be explained by a difference in cell-cycle distribution,
by different sensitivity to CD40 cross-linking, or by a general
resistance to apoptotic pathways, as the perforin/granzyme pathway
of cytotoxic T cells proved to be operative [
130
]. Therefore,
blocks within the specific intracellular signaling must be assumed
to be a common feature of B cell lymphomas, dissociating Fas
expression and sensitivity.
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Table 3. Expression and Functional Status of Fas in Lymphatic Neoplasias and Their Correlation with Clinical Parameters
|
In contrast, myeloma cells seem to have preserved an intact
Fas-signaling machinery, at least in some cases, suggesting
that by regulating Fas expression levels, sensitivity may be
regulated. Indeed, the degree of Fas expression has been correlated
with Fas sensitivity in this disease [
143
,
148
,
149
], and
Fas expression levels decline during the progression of monoclonal
gammopathy of undetermined significance to myeloma and plasma
cell leukemia [
143
]
(Table 3)
. This is in good concordance
with other tumor models in which down-regulation of Fas enables
escape from immune surveillance.
Mutation of the receptor
Mutations within the fas gene were identified in 11% of 150 cases of NHL examined [139
]. Most of the mutations found were believed to interrupt a functional signaling cascade along the Fas pathway. The highest frequency of fas mutations was seen in MALT–NHL, and almost all patients with mutations showed extranodal disease (Table 3)
. Strikingly, most patients with fas mutations showed clinical features of autoimmunity consistent with the expectations from murine lpr models and from patients with ALPS who showed an accumulation of CD4-/CD8- T and autoreactive B cells and features of autoimmunity [150
]. Mutations within the cytoplasmic region of the fas gene responsible for successful signal transduction were also shown to occur in 10% of myeloma patients [144
] but were quite rare in other hematopoietic tumors [134
].
Intracellular equipment with constituents of death receptor signaling
Other strategies of B cell neoplasias to evade lethal Fas signals are related to alterations in constitutents of the Fas signaling cascade. Oligonucleotide microarray analyses of mantle cell lymphoma show a more than tenfold down-regulation of the FADD adaptor molecule [151
]. The involvement of members of the Bcl-2 family in the signaling pathway of Fas may vary depending on the cellular background examined (i.e., type I vs. type II cells; ref. [9
]). Bcl-2 is expressed at high levels in myeloma cells, but unlike Bax [148
], its expression does not correlate with Fas sensitivity [148
, 152
]. BcL-XL levels were increased in myeloma cells [153
], and IL-6-induced up-regulation contributed to resistance to apoptosis [154
]. In the vast majority of Hodgkin cases [127
], the neoplastic Reed-Sternberg (RS) cells express Fas [70
, 155
] (Table 3)
. The intact equipment with the constituents of the apoptotic machinery and histological finding of signs of apoptosis in some RS cells point to Fas sensitivity at least in some cases. The survival of most RS cells may be a result of the down-regulation of caspase-3 and -8 [156
] or an altered cell-cycle behavior [157
] with a short pause in the usually Fas-sensitive, late G1 or G1/S transition phase [158
].
Soluble factors and cytokines
Investigations about the role of cytokines on Fas sensitivity, partially preserved in myeloma, pointed to the presence of protective factors in sera of myeloma patients and normal individuals [143
], and paracrine IL-6 was identified [159
, 160
] as one of these cytokines. Also, autocrine IL-6 proved protective against anti-Fas mAb-induced apoptosis [161
]. Paracrine and autocrine IL-15 [161
] also counteracted Fas signaling and protected myeloma cells from Fas-induced apoptosis. As IL-15 is usually considered as a factor that promotes growth, differentiation, and activation of T and NK cells acting against tumor cells, these data suggest that acquisition of a T cell growth and survival factor by tumor cells helps them to evade the immune system. Different results were reported for therapeutically applied cytokines such as IFN-. By interference at the level of protein kinase C, this cytokine mediated resistance to Fas-induced cell death when applied simultaneously or before cross-linking of Fas [162
], whereas prolonged incubation with IFN- [162
] or IFN- [163
] induced Fas up-regulation and rendered myeloma cells susceptible to Fas-mediated apoptosis [163
]. These results suggest that the protective versus survival effects of cytokines on the modification of Fas/FasL interaction depend on the concentration, duration of stimulation, and thus, on the humoral microenvironment in vivo. In addition, some myeloma cell lines are sensitive to cross-linking of Fas by anti-Fas mAb but resist apoptosis by FasL+ allogeneic T cell lines [97
]. This points to a specific self-protection during cell/cell contact, which at least in part could be a result of or augmented by the release and autocrine action of protective cytokines.
THERAPEUTIC INTERVENTIONS TARGETING THE DEATH RECEPTOR PATHWAYS
Any attempt to modulate or revert the mechanisms of immune evasion
of tumor cells as a consequence of their down-regulation of
Fas and/or TRAIL-R sensitivity or FasL-/TRAIL-mediated suppression
of immune effector cells must take into consideration the complex,
pathological changes in the communication between these cell
types, the importance of the Fas/FasL system in normal immune
and organ functions, and the heterogeneity of aberrations in
the various leukemias and lymphomas. From mice experiments,
it soon became clear that sFasL would have to be disregarded
from direct, therapeutic considerations as a result of its severe
and sometimes lethal hepatotoxic side-effects [
164
]. However,
even an indirect use and redirection of the Fas pathway might
turn out to be unexpectedly dangerous. For instance, drug-induced
toxic epidermal necrolysis has been shown to result from the
up-regulation of the Fas/FasL system in keratinocytes with their
subsequent induction of auto- and/or paracrine suicide [
165
].
This example contains an implicit caveat, not only against modification
of Fas signaling during cancer treatment but also against targeting
other death receptors such as TRAIL, which uses highly similar
signaling pathways. Furthermore, an exact understanding of the
molecular basis of the differential sensitivities of normal
and neoplastic tissues is lacking (see below). In any case,
strategies for sensitization of tumor cells to death receptor
signaling have to be clearly separated from attempts to antagonize
deleterious effects resulting from death receptor, ligand-bearing
tumor cells or from using FasL or TRAIL during therapeutic maneuvers
such as allogeneic transplantation. It would not be surprising
if the latter turns out to be the more realistic strategy.
Interventions targeting Fas or TRAIL-R signaling cascades of tumor cells
Attempts to increase the sensitivity of tumor cells along the Fas pathway may in principle aim at two different aspects: namely resensitization to FasL+ or TRAIL+ effector cells and simultaneously, to cytotoxic drugs, as the signaling cascades used are partially overlapping. Briefly, the strategies mentioned below might be followed.
Up-regulation of Fas on tumor cells
Previous experiments have demonstrated that the degree of Fas expression is directly correlated with [148
] or even represents the major determinant of Fas sensitivity in myeloma cells [166
], and a number of diverse approaches have successfully been applied to increase the sensitivity in many tumor types [163
, 167
168
169
]. At least in myeloma, this sensitization was probably a result of simultaneous up-regulation of proapoptotic molecules such as Bax [148
]. Although up-regulation of Fas via IL-12 sensitized CLL cells to FasL-bearing, autologous T cells [170
], up-regulation of Fas was not uniformly associated with sensitization. More complex maneuvers including stimulation of CD40 were required for sensitization of CLL cells to Fas up-regulated via IL-15 [171
]. In addition, it has to be stressed that the in vivo effects may be much more complex, as a given cytokine such as IFN- had completely opposite effects on myeloma cell sensitivity to Fas in the short and long run [162
, 163
]. Moreover, the sequence of cytokine signaling may be important to predict their effect on Fas-induced cell death. Indeed, auto- or paracrine IL-6, while inhibiting Fas-induced myeloma cell death, significantly increased Fas expression and Fas sensitivity of these cells following their treatment with IFN- [172
]. Similarly, the effect of a given cytokine may be completely opposite, depending on the tumor-specific maturation stage. IL-15 might up-regulate Fas and sensitize cells to Fas-induced apoptosis when acting in concert with CD40L in CLL [171
] and at the same time, protect myeloma cells from Fas-induced cell death [161
]. Therefore, knowledge of disease-specific tumor biology must guide attempts to up-regulate Fas signaling by using cytokines such as IL-12 [170
, 173
] and antibodies counteracting cytokines such as IL-6, IL-15 [161
], or IL-4 and/or histone deacetylase inhibitors [174
].
Resensitization to Fas signaling by CD40 stimulation
Given the paramount importance of the CD40L/CD40 system for the induction of specific T and B cell responses of the FasL/Fas system for limiting inappropriate stimulation and the expansion of autoreactive T cells, it is not surprising that cells carrying components of these two systems interact within the normal germinal center and that signaling events along these two receptor systems are interdependent or crossing. During the transit through the germinal center, B cells develop profound changes in apoptosis regulation [175
] and so do their relevant neoplastic counterparts. It is therefore not surprising that interactions between the CD40/CD40L and the Fas/FasL system might be heterogenous according to the relevant differentiation stage of neoplastic B cells, and this might impact on the capacity of the T cell system to control the tumor. For example, CLL cells usually express extremely low amounts of Fas, and CD40L stimulation of cultured B-CLL cells leads to up-regulation of Fas, but tumor cells continue to resist death as a result of a simultaneous increase in the expression of FLIP [176
] or survivin [177
]. Autologous serum of patients rescues cultured CLL cells from death, an effect, which is in part a result of sCD40L and can be counteracted by anti-CD40L antibodies [178
]. The antiapoptotic effect of CD40 signaling may partially be explained by its potential to stimulate secretion of growth-promoting and apoptosis-inhibiting cytokines such as IL-6, as demonstrated in myeloma [179
]. Besides protection from Fas-induced cell death, CD40 signals inhibited induction of cell death by fludarabine in CLL cells [180
] and by doxorubicin in NHL cell lines [181
]. In addition, a proliferative potential of CD40L has been demonstrated in mantle cell lymphomas [182
]. These results should discourage the use of CD40 stimulation as a therapeutic tool in attempts to resensitize cells to Fas. However, mantle cell lymphoma, CLL and ALL cells, cell lines [183
], and native cells of B cell NHL [184
] as well as the majority of Burkitt lymphoma cell lines [167
] not only up-regulated Fas but also became sensitive to FasL when stimulated by CD40L. Exploitation of this mechanism with a therapeutic intent showed efficacy in elegant xenograft models of high-grade lymphomas [185
, 186
] using oral CD40L gene therapy or agonistic mAb.
These somewhat contradictory results might be explained by the fact that in vivo effects of CD40L are of a pleiotropic nature. In fact, the induction of a specific and successful immune response to CLL cells might be initiated by a transfection of CD40L into CLL cells, which are then retransferred into the bloodstream of the patient [187
]. The increase in immunogenicity might in part be a result of induction of members of the cytokine network such as IL-15, which like CD40L, up-regulates Fas and when acting in concert with CD40L, sensitizes these cells to Fas [171
]. In addition, up-regulation of CD80 and CD86 on antigen-presenting cells may induce effector mechanisms of T cells against the neoplastic clone, which might not be observed when signaling interferences between Fas and CD40 are studied only in vitro.
Although some of these results seem encouraging, the pleiotropic effects of the CD40/CD40L interaction and the significant differences observed between high-grade lymphoma models (beneficial) versus subtypes of low-grade lymphoproliferative diseases (reviewed in ref. [188
]) suggest that caution must be exercised in early in vivo trials of CD40L therapy with or without attempts at Fas-resensitization [189
]. These should be accompanied by rigorous examination of the biological basis of the results observed. Keeping these caveats in mind, a phase I clinical trial with recombinant CD40L (Avrend®, Immunex, Seattle, WA) was performed only on patients with intermediate and high-grade NHL. It demonstrated an 11% response rate in this disease when used as a single agent [190
]. No evidence of disease acceleration was observed during treatment [189
]. These results encourage and justify use of this drug as a monotherapy in high-grade NHL in phase II trials and in combination with death receptor agonists in preclinical experiments. In low-grade NHL and CLL, the complex induction of sensitivity against FasL+ effector cells may be more reasonable than direct use of CD40L.
Direct intervention by death receptor agonists and modification of the intracytoplasmatic signaling machinery
In principle, therapeutic exploitation of signaling along the Fas and TRAIL pathway may be accomplished by several means, namely, by the use of recombinant ligands of the receptor or by designing specific agonistic antibodies (Fig. 2
). Both approaches are currently being investigated. The choice of an adequate technical tool as well as the attempt to specifically address the Fas or the TRAIL pathway may be determined by side-effects and toxicity profiles of the tools and the relevant degree of efficacy in a specific lymphatic neoplasia.
Fas-agonistic molecules.
Systemic application of recombinant FasL or cross-linking of
Fas by mAb had to be stopped at the earliest phase as a result
of the observation of lethal hepatotoxicity in mice [
164
].
Recently, however, a new anti-Fas mAb (clone HFE7A) has been
developed, which in contrast to other agonistic antibodies,
did not cause liver injury in mice [
192
], and it efficiently
killed Fas-transgenic splenocytes in a severe combined immunodeficiency
(SCID) mouse model, thereby protecting them from severe graft-versus-host
disease (GvHD) [
193
]. This mAb has now been humanized and tested
for its efficacy in a human rheumatoid arthritis/SCID mouse
model, where it was shown to kill activated T cells only after
cross-linking via a secondary antibody or by binding Fc receptor
for IgG (Fc
R)-bearing effector cells. Normal chondrocytes remained
unaffected [
194
]. Given the different roles of Fas and TRAIL
in the regulation of physiologic B and T cell expansion and
of their aberration in lymphoma genesis, this approach deserves
further preclinical development.
Recombinant human (rhu) TRAIL.
TRAIL is a promising candidate for therapy of some hematopoietic tumors, as its agonistic receptors DR4 and DR5 are expressed in a wide variety of tumor cells, rendering them sensitive to its proapoptotic action, and normal tissues, in particular, hematopoiesis, are usually protected, despite the somewhat controversial results in the erythroid lineage [38
, 76
, 77
, 195
] (Table 1) . Furthermore, Apo2L/TRAIL effects can be augmented by chemotherapeutic agents and ionizing irradiation [38
, 195
196
197
] without increasing toxicity on normal hematopoiesis [77
]. Synergism with cytotoxic agents may also be indicated by the observation that treatment of AML M3 cells with retinoic acid induced TRAIL expression, which was involved in paracrine killing of leukemic cells and in elimination of retinoic acid-resistant leukemic cells [198
]. Similarly, IFN--induced autocrine suicide of lymphoma cells proceeded via TRAIL [50
] (Table 2)
. Myeloma seems to be a candidate disease for treatment with TRAIL, particularly as the high intrinsic expression levels of Bcl-2 and BcL-X do not interfere with sensitivity. In fact, ectopic Bcl-2 overexpression failed to block TRAIL-induced apoptosis in cell lines [199
]. TRAIL sensitivity was further enhanced by treatment with IFN- and -ß [52
], NF-B, or proteasome inhibitors and doxorubicin [53
]. These substances are part of clinical practice or tested in early clinical trials (see below and Table 4
). Results were confirmed in native material and in xenotransplanted nu/xid/bg mice [53
]. TRAIL has also been tested in vitro in a limited range of other hematological neoplasias, and sensitivity of tumor cells has been reported to a lower degree (Table 2)
.
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Table 4. Selection of Antiapoptotic Reagents Important in the TRAIL and/or the Fas Signaling Pathway and at the Interface of Action of Immunological Effector Cells and Cytotoxics: Status of Development for Clinical Application
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To be useful as a therapeutic agent, a cytotoxic substance should
cause as little harm as possible to normal tissue. The clinical
usefulness of TRAIL seems to be supported by in vitro data mentioned
above and results from preclinical xenograft models, which demonstrate
a selective killing of various human tumor cells by TRAIL [
195
,
206
]. However, subsequent studies with different chemical modifications
of TRAIL have cast doubt on this optimistic view and have raised
serious concerns. Although histidine-tagged TRAIL may be more
efficacious than TRAIL lacking exogenous tags Apo2L-TRAIL.0
[
207
] in terms of tumor cell killing [
203
], the histidine-tagged
variant proved toxic to normal hepatocytes [
208
]. Attempts
to facilitate and stabilize the oligomerization of TRAIL by
inclusion of a leucine-zipper motif led to toxicity against
astrocytes [
195
], and a similar neurotoxic effect resulted
from the use of a FLAG-tagged version of TRAIL [
209
]. A detailed
study by Lawrence et al. [
207
] revealed that Apo-2L/TRAIL.0
was nontoxic to normal human and monkey hepatocytes, and the
histidine-tagged version proved toxic in the same types of cells,
probably as a result of its irreversible binding to the receptor.
Analyses in cynomolgus monkeys or chimpanzees revealed that
Apo-2L/TRAIL.0 could be safely administered intravenously without
significant changes in clinical pathology including liver enzyme
activities. Similarly, the direct injection of unmodified rhu
TRAIL into murine brain, alone or in combination with SMAC peptides,
proved nontoxic in the short as well as in the long run [
203
].
Agonistic anti-TRAIL-R antibodies.
Two agonistic mAb have been developed, which selectively bind to TRAIL-R1 and TRAIL-R2 on hematopoietic and solid tumors (Table 4) . In contrast to rhu TRAIL and the physiological ligand to TRAIL-R1 and -R2, the agonistic anti-TRAIL-R1 mAb does not bind to DcR1 and DcR2 or the soluble receptor osteoprotegerin, all of which act as decoy receptors. In addition, the antibody has a significantly longer serum half-life as compared with the natural ligand. These features make agonistic antibodies an interesting and attractive tool for further development and in fact, patients are being recruited for phase I trials with agonistic anti-TRAIL-R1 mAb (Table 4)
, and agonistic anti-TRAIL-R2 mAb is under advanced preclinical investigation (Table 4)
.
Use of FasL and TRAIL for graft-versus-tumor (GvT) effects.
The potency of the immune-effector mechanisms is apparent in the clinical manifestation of allogeneic hematopoietic cell transplantation. The success of allogeneic transplantation depends on a delicate balance among host-mediated graft rejection, the desired GvT effect, and the detrimental GvHD induced by donor lymphocytes. The kind of effector mechanisms involved in the interaction between host’s and donor’s immune cells seems to depend on whether human leukocyte antigen-matched, major histocompatibility complex (MHC)-disparate, or minor histocompatibility antigen-mismatched allogeneic transplantations are performed, as well as on the degree of host T cell depletion caused by the conditioning regimen. Host CD8+ and NK cells serve as a barrier against the donor hematopoiesis and the transplanted lymphocytes [210
]. Experiments with perforin or perforin/FasL double-deficient mice demonstrate that donor-mediated cytotoxicity has a role to play in enabling engraftment [211
]. Under nonmyeloablative-conditioning regimens, the expansion of donor CD4+ cells in the early post-transplantation period crucially relies on their FasL expression to defend themselves against the host-versus-graft effect [212
]. In addition, viral transfection of donor lin- BM cells with FasL protected the donor graft from acute rejection without acute hepatotoxicity, myelosuppression, and immunosuppression [213
]. Transplantation of FasL-defective donor T cells leads to a mixed chimerism in the murine recipient [214
], pointing to the contribution of the FasL system for elimination of residual host hematopoiesis surviving total body irradiation and for the successful expansion of donor hematopoiesis. In contrast, FasL expression on donor effector cells may also be deleterious, as Fas expression on hematopoietic cells occurs within 2 weeks after the induction of acute GvHD, probably via stimulation by IL-12 and IFN-, and CD4+ cytolytic T lymphocytes mediate BM failure in a FasL-dependent manner [215
]. Furthermore, post-transplant lymphoid hypoplasia and B cell dysfunction are linked to an intact FasL [214
]. Inactivation of FasL on donor lymphocytes by mutation [216
] or antagonistic mAb [217
] led to reduced cytotoxicity against the host liver and skin. Although the contribution of the FasL system to the extent, pattern, and morbidity/mortality of GvHD varied in the different models examined, transplantation of FasL-mutated donor lymphocytes was associated with prolonged life of the allogeneic host in at least one report [218
].
The GvT effect has usually been attributed to CD8+ cells and their equipment with perforin and granzyme, as CD8+ cells were thought to act primarily through granule-dependent mechanisms, and perforin-/- mice are characterized by profound disturbances in the immune surveillance of tumors [219
]. Recent investigations, however, suggest a more complex mechanism of action. In a strictly tumor antigen-dependent, syngeneic murine model, GvT effects were mediated by CD4+ and CD8+ cells, but the former acted primarily via FasL and secondarily via perforin, and the situation was the reverse in CD8+ cells [220
]. These analyses demonstrate that there is a redundancy in the effector mechanisms, as they were not restricted to certain types of T cells but rather preferentially used by them. The existence of individual MHC class I- or II-restricted tumor antigens can be postulated to direct the preferential use of effector systems in T cell subsets [220
]. In an allogeneic transplant model, the GvHD mediated by CD4+ and CD8+ cells mostly involved the Fas/FasL system, but the GvT effects were strongly dependent on an intact perforin system in CD8+ cells [221
]. Such a preferential involvement of effector systems rather than of executioner cell types in GvT or GvHD suggests certain possibilities for therapeutic exploitation. In fact, the inhibition of release of FasL (or TNF-) by treatment with a metalloproteinase inhibitor prevents lethal, acute GvHD in a murine system [222
] and anti-FasL antibodies block BM failure induced by FasL+ CD4+ effector cells [215
]. Even more important, it was recently demonstrated that inactivation of the FasL not only helped to ameliorate acute GvHD but at the same time, left the GvT effect intact [223
]. This dissociation of GvHD from GvT effects was achieved without maneuvers for inhibiting TNF- or the perforin granzyme pathway. Therefore, interference with the Fas/FasL system might be further developed to an efficient way of handling acute GvHD by dissociating GvHD from GvT effects. Finally, genetically modified effector cells might also be used therapeutically. In a very elegant approach, donor T cells were successfully equipped with a conditional suicide mechanism in the form of a chimeric protein consisting of the intracellular signaling domain of Fas, an extracellular marker, and two copies of an FK506-binding protein [224
]. These cells expressed the chimeric protein stably, preserved their immunologic functions in specific alloantigeneic response, and were killed by application of subnanomolar concentrations of a bivalent dimerizer inducing the apoptotic signaling of Fas. Alone or in conjunction with attempts to target the TNF effects [223
, 225
], such strategies may be used to downsize untoward side-effects and to direct T cell functions more specifically in allotransplantations.
The observation that T cells deficient for FasL and perforin still exerted GvT activity [226
, 227
] suggested that other effector mechanisms were also involved. A systemic investigation of the role of TRAIL in GvT effects uncovered its important role in donor T cell-mediated GvT activity [228
]. Although TRAIL-deficient T cells showed significantly lower GvT activity, no significant differences could be observed in GvHD. From experiments comparing the outcome of transplantation of wild-type-, perforin-/--, or TRAIL-/--purified T cell fractions, the authors concluded that perforin and TRAIL are required for optimal GvT activity by T cells, with a greater relative contribution observed for the perforin pathway [228
].
Modification of the cytoplasmatic machinery for enhancement of death receptor stimulation.
In tumors primarily sensitive to death receptor ligands as a result of an intact receptor expression and signaling cascade along the type I and type II pathway (previously discussed), TRAIL or agonistic death receptor mAb against TRAIL-R or Fas might be directly used as single agents (Fig. 2)
. Unfortunately, however, many tumor types including lymphatic neoplasias display resistance to TRAIL and other death receptor ligands (Table 2) as a result of a number of aberrations within their signaling pathway. For example, reduced expression of caspase-3 and -8 seems frequent in HD [156
], and transfection of a caspase-3-deficient Hodgkin cell line with the caspase-3 gene rendered the cells sensitive to Fas, TRAIL, and Ara-C [49
]. Transfection of caspase-8 in EBV type III+ Burkitt lymphoma cell lines or genetic manipulation with alteration of their caspase-8/FLIP ratio resensitized these cell lines, which are often Fas-resistant [229
]. In addition, antagonists of Fas/TRAIL-R signaling pathways such as Bcl-2, Bcl-XL, IAPs, XIAP, and survivin are (over)expressed in neoplastic but not in normal cells [230
], and such overexpression is associated with an unfavorable prognosis in some tumor types. Although transfer of proapoptotic genes or inhibition of antiapoptotic genes by antisense strategies have proven effective in some preclinical xenograft models, these treatment programs are often hampered by their low effectiveness in systemic diseases, as they are even in localized diseases. Thus, technical improvements in gene-targeting strategies have to be awaited. Fortunately, however, substantial progress has recently been achieved in the development of the antisense technology and the computer-assisted design of small, permeable agonistic or antagonistic molecules, which interfere with the death machinery of tumor cells important for an intact signaling along death receptors. These molecules presented in Fig. 2
and Table 4
might be useful for the development of a tumor-specific, resensitization program toward death receptor agonists within the various subtypes of lymphatic neoplasis.
In conclusion, the intrinsic antitumor activity together with the additive or synergistic action with other anticancer agents make TRAIL or agonistic death receptor mAb promising candidates for targeting death receptors in lymphoma cells. The fact that resensitization toward TRAIL and Fas may be accomplished by a rather broad spectrum of approaches currently in preclinical or clinical development should also be a source of optimism.
Targeting FasL on tumor cells
Given a suppressive and deleterious role of naturally occurring, tumor-associated mFasL on the survival and function of many cell types in the natural microenvironment of the tumor (Fig. 1) , it is an attractive strategy to target the expression of mFasL and/or its effects at the site of the presumptive targets of the death signal. There are several approaches that deserve interest. Antisense oligonucleotides or transfection of more localized hematological tumors by FasL antisense DNA might be used; the latter approach has successfully reduced tumor growth and combatted the tumor counterattack in mice xenografted with colon cancer cells [231
]. The recent successful development of mAb strategies against cytokines also favors the approach of counteracting mFasL in its soluble form by antibody strategies and decoy receptors. Neutralizing anti-FasL mAb alone or in combination with anti-TNF- mAb has been tested in a lethal, acute graft-versus-host model of allogeneic BM transplantation in mice [217
]. Some clinical features of this disease, in particular hepatic and skin lesions, are mainly caused by FasL-bearing effector cells in the graft (reviewed in R. Greil et al., submitted for publication); and FasL targeting significantly reduced hepatic, cutaneous, and splenic lesions, and anti-TNF- mAb preferentially suppressed gastrointestinal manifestations of the disease. When used together, anti-FasL and anti-TNF- mAb provided complete protection from death [217
]. Detailed histological examinations revealed that antagonistic mAb blocked the massive infiltration of inflammatory cells (mainly neutrophils) and prevented elimination of host lymphocytes (T and B cells), presumably through inhibition of activation-induced cell death, in which FasL and TNF- have been implicated.
Other attempts may focus on protecting the target, e.g. by down-regulating Fas or inhibiting the signaling machinery downstream of the receptor. Such an attempt might decrease sensitivity of tumor cells to Fas and therefore be interesting in situations where the tumor is primarily inaccessible to Fas signaling but sensitive to treatments unaffected by alterations of the Fas signaling pathway. Very recently, stress has been shown to deplete murine spleens from lymphocytes via a Fas-dependent pathway and the stress-induced changes in Fas expression and sensitivity, and the decrease in splenocyte numbers could be inhibited by opioid-receptor antagonists such as naloxone or naltrexone [232
]. Such strategies should be investigated in greater detail in xenograft models of hematopoietic tumors and their efficacy in protecting normal hematopoiesis and immunocompetent cells, and other cells of the microenvironment should be evaluated.
CONCLUDING REMARK
The initial aim of the investigations was to examine the role
of the Fas/FasL and TRAIL/TRAIL-R systems in the regulation
of immunocompetent cells and their interplay with potential
target cells. Since then, multiple and complex mechanisms have
come to light by which tumor cells evade specific death signals,
acquire and adapt molecules originally developed by nature to
defeat tumor cells, and finally, use these alterations in the
death receptor/ligand system to suppress immunity and hematopoiesis.
It is to be hoped that the lessons learned from these interactions
as well as from the interplay between death receptor signaling
and efficacy of cytotoxic agents add to our store of knowledge
and contribute to the development of effective therapeutic strategies
that target Fas and TRAIL.
ACKNOWLEDGEMENTS
R. G., I. T., and G. A. were supported by grants from the OeNB
Nr. 8222, the Austrian Science Foundation (T95-PAT, P16153),
The Province of Tyrol, the Tyrolean Cancer Aid, the Austrian
Cancer Aid, and the Verein für Klinische Malignom und Zytokinforschung.
G. A. was supported by the Austrian Academy of Sciences.
Received August 27, 2002;
accepted March 25, 2003.
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