melanoma
and breast carcinoma lesions analyzed (Vitale et al, 1998; Kageshita et al,
1999). TAP downregualtion in breast carcinoma, small cell lung cancer (SCLC),
cervical carcinoma and melanoma lesions have been found to be associated with
disease progression (Keating et al, 1995; Vitale et al, 1998; Hicklin et al,
1999). Tapasin which plays an important role in the assembly of MHC class I molecules
with peptides in the endoplasmic reticulum, is also downregulated in high
frequencies and associated with progressive disease in melanoma (Dissemond et
al, 2003).
C. b2m
In addition there appears to be a role in selective
immune pressures in the generation of HLA I mutations and loss of HLA I. In vitro, it has been described that
tumor cells with HLA I defect will out grow normal HLA I antigen presenting
tumor cells when exposed to CTL recognizing the allospecific HLA I antigen. On
the contrary, when these same tumor cell population are grown in an
immunologically na•ve environment, cell grow appears similar. These findings
support the clinical findings of increased frequency of HLA I losses in
malignant lesions of patients treated with T cell-based immunotherapy (Restifo
et al, 1996).
D. MHC
class I Chain-related Molecules (MIC)
Epithelial tumors that shed MHC class I chain-related
(MIC) molecules escape from NK and T cell recognition (Diefenbach and Raulet,
2002). MICs are ligands for the activating receptors NKG2D on both NK and T
cells. It has been reported that elevated serum levels of soluble MIC in
colorectal cancer are responsible for the down-modulation of NKG2D as well as
chemokine CXCR1. In vitro,
internalization of NKG2D and CXCR1 occurs within 4 and 24 h, respectively, of
incubating normal NK cells with sMIC-containing serum and the addition of
anit-MIC-Ab lead to an up-regulated expression of NKG2D, CXCR1 and CCR7. These
results suggest that circulating sMIC in patients with cancer deactivates NK
immunity by down-modulating important activating and chemokine receptors (Groh
et al, 2002; Doubrovina et al, 2003; Lanier, 2003).
E.
MHC Class II molecules
Although not as predominantly expressed as MHC class I
molecules, MHC class II molecules may be expressed by tumor and elicit a CD4+
Tcell antitumor immune response via a professional APC (Wang, 2001).
Alterations in the presentation of peptides on MHC class II may affect the
generation of effective CD4+ T helper cell antitumor response. Defects
have been noted at the AIR locus, which encodes the transcription factor and
class II transactivator (CIITA) thus effecting expression of MHC class II
antigens.
F. Escape from NK immune
surveillance
The role of NK cells is to monitor
cells for their expression of self-MHC molecules via their specific KIR
receptors and eliminate those cells with downregulated or loss of MHC class I
(Moretta et al, 1996). Because most tumor cells have little to no MHC class I
expression, NK cells have a significant function in the antitumor response.
Data from mutant mouse models lacking distinct immune cell populations develop
spontaneous tumors (Dunn et al, 2002). With respect to the tumors, many studies
have demonstrated that MHC class I deficient transplantable tumor cell lines
are rejected by NK cell (Ljunggren and Karre, 1985; Piontek et al, 1985;
Taniguchi et al, 1985), and restoration of MHC class I expression reversed the
effect (Franksson et al, 1993). In addition, tumor cells frequently express
families of stress-related genes such as MICA and MICB which function as
ligands for NKG2D receptors expressed by NK cells and other cytotoxic
lymphocytes and phagocytes (Diefenbach and Raulet, 2002).
Even though downregulation or loss of MHC class I cell
surface expression should make tumor cells more susceptible to NK immune
effector mechanisms, tumor cells continue to proliferate and invade. Patients
with cancer have exhibited ex vivo
impaired NK-cell function as determined by reduced proliferation, response to
interferons (IFNs) and cytotoxicity (Whiteside and Goldfarb, 1994; Trapani et
al, 2000). One possible mechanism by which tumor cells evade NK cell killing is
by the continued expression of appropriate MHC class I ligands that engage
inhibitory receptors on NK cells (Tajima et al, 2004). NK cells are also
affected by the tumor cells secretion of immunosuppressive factors (discussed
below).
III. Tumor release of immunosuppressive factors
It has been well known but not thoroughly understood
that lymphocytes recovered from both the peripheral blood, as well as the
tumors themselves, in patients with malignancies are functionally compromised.
These lymphocytes can also be further characterized to have tumor-antigen
specific responses although do not induce apoptosis or tumor cell death. Tumor
cells create a microenvironment by expressing or secreting several different
cytokines and growth factors to induce immune suppression.
A.
IL-10
IL-10 has been described to be secreted by tumor cells
to cause an effective immunosuppression of infiltrating T cells. IL-10 exerts
an indirect effect on the immune system by inhibiting the secretion of
proinflammatory cytokines like IL-1, IL-6, IL-8 and TNFa (Tsuruma et al, 1999), free oxygen radicals, nitric
oxide derivatives from type 1 helper T cells, monocytes, macrophages and
neutrophils, and inhibiting the secretion of IFNg by NK cells (Moore et al, 1993). Furthermore, IL-10
downregulates MHC class I, II and B7 molecules (Matsuda et al, 1994;
Salazar-Onfray et al, 1997), all of which are important for the induction of
the antigen-presenting capacity of macrophages and dendritic cells and
activation of T cells. There have been many reports of IL-10 production of a
variety of solid tumors such as carcinomas of the colon, lung and skin (Gastl
et al, 1993; Huang et al, 1995). Increased levels of tumor derived IL-10 has
been reported in plasma of patients with NSCLC and correlated with decreased
survival (Neuner et al, 2001).
B.
COX
COX (cyclooxygenase or PG endoperoxidase) is a
rate-limiting enzyme involved in the production of prostaglandins and
thromboxanes from free arachidonic acid. Two forms of this enzyme have been
described: COX-1 which is constitutively expressed in most cells and tissues,
and COX-2 which is induced by cytokines, growth factors and other stimuli
(Herschman, 1996). COX-2 is constitutively overexpressed in a variety of
malignancies (Soslow et al, 2000) and has been to enhance tumor resistance to
apoptosis (Tsujii and DuBois, 1995), increase angiogenesis, invasion and metastasis
(Leahy et al, 2000; Dohadwala et al, 2001) and impair host immunity {Huang,
1998 #34} (Stolina et al, 2000). In regards to the immune systems, the
overexpression of COX-2 has been reported to significantly enhance a
PGE2-dependent IL 10 production by macrophages, dendritic cells and lymphocytes
as well as decrease IL-12 production. In addition, tumor COX-2 lead to a
suppression of dendritic cell function by decreasing the dendritic cell
capacity to process and present antigens and induce alloreactivity as well as
alter the dendritic cell phenotype to an immature phenotype with decreased
expression of CD11c, CD80, CD86, MHC class I and II (Sharma et al,
2003). When T cells and dendritic cells from patients with breast cancer were
evaluated, their function directly correlated with COX-2 and PGE2
overexpression. T cells demonstrated a decreased proliferation in response to
CD3 antibody stimulation, reduced production of interferon g, TNF-a,
IL-12, IL-2 and increased levels of IL-10 and IL-4. Dendritic cells revealed a
reduced expression of co-stimulatory molecules, reduced phagocytic ability and
reduced antigen presentation as well (Pockaj et al, 2004).
C.
TGF-b
Transforming growth factor-beta (TGF-b) is overexpressed by numerous malignant tumors such as
breast cancer, prostate cancer, small and non-small lung cancer, colorectal
cancer, pancreatic cancer, ovarian cancer, bladder cancer, melanoma and
malignant gliomas (Wojtowicz-Praga, 2003). TGF-b is a potent immunosuppressor, helping tumor cells
evade the immune system. A second role of TGF-b is to stimulate angiogenesis further promoting tumor
growth. TGF-b is known to activate cytostatic gene responses at any
point the cell cycle, especially G1
as well as repress growth-promoting transcription factors. Although TGF-b can induce apoptosis in hematopoetic cells (Siegel
and Massague, 2003), tumor cells become refractory to TGF-b-mediated growth arrest by either the loss of TGF-b receptors, mutation in the receptors or due to
dysregulation in TGF-b signaling pathways
whereas immune cells remain sensitive (Wojtowicz-Praga, 2003). TGF-b interacts with T cells to efficiently block their
IL-2 production and proliferation (Chen et al, 2003). In addition, it
interferes with the generation of CTL, inactivates NK cell and lymphokine
activated killer cell cytotoxicity most likely by the inhibition of TNF-a and b
secretion (Gray et al, 1994, 1998; Ebert et al, 1999). Dendritic cell
maturation and antigen presentation is also impaired by TGF-b (Geissmann et al, 1999), and TGF-b produced by tumors significantly reduced the potency
of DC/tumor fusion vaccines (Kao et al, 2003). Furthermore, TGF-b may have a pivotal role in inducing immune
suppression by CD4+/CD25+ regulatory T cells (Wahl et al,
2004).
The mean concentration of IL-10 and TGF-b were evaluated in patients with
pancreatic ductal adenocarcinoma and noted to be considerably higher than in
control serum. In that same study TILs were analyzed and shown to have a severe
loss of CD3 z chain
correlating to the increased levels of IL-10 and TGF-b. Killing of tumor cells by
potentially cytotoxic TILs appeared to be suppressed by the prevention of a
direct TIL/tumor cell contact and the inactivation of TILs, as shown by a loss
of CD3 z (von
Bernstorff et al, 2001).
D.
B7-H1
In addition, tumors can actively inhibit immune
responses by expressing a B7 homolog-1 (B7-H1) which is known as a programmed death ligand 1.
B7-H1 is expressed on many tumors including carcinomas of the breast, lung,
ovary and colon, whereas normal tissues do not express B7-H1. Their expression
can interact with the CD28 receptor on CTLs and promote CTL death
via induction of Fas Ligand and IL-10 {Dong, 2003 #6}.
E. VEGF
Vascular endothelial derived growth factor (VEGF) may
be produced by tumor cells, which promotes tumor angiogenesis but inhibits the
immune cell function by impairing both the effector function and early stages
of hematopoiesis. VEGF receptors are present on early hematopoetic progenitor
cells (Ferrara, 1996). Almost all tumor cells produce VEGF; elevated levels are
frequently detected in the sera of cancer patients and these elevated levels
are associated with a poor prognosis (Dikov et al, 2001). VEGF causes a defect
in the maturation of dendritic cells from early hematopoetic progenitor cells
(Gabrilovich et al, 1998). In addition, mice treated with continuous infusion
of recombinant VEGF have a decreased number of T cells and a decreased
T-to-B-cell ratio in their lymph nodes and spleen (Ohm and Carbone, 2002; Ohm
et al, 2003).
IV.
Decreased sensitivity of tumor cells to immune-mediated apoptosis
It is well known that human cancer cells have
dysfunctional apoptotic pathways leading to the resistance of these cells to
apoptosis by therapeutic agents. In addition, impairment of the apoptotic
signaling pathway plays an important role in the initiation and progression of
normal cells into cancer cells (LaCasse et al, 1998; Reed, 1999; Hickman,
2002). In the last several years we have gained much incite on the individual
cellular factors involved in apoptosis as well as their roles in the apoptosis
pathways. The two main pathways involved in apoptosis are the extrinsic pathway
and the intrinsic pathway. In brief, the extrinsic pathway of apoptosis is
initiated by the interaction of cellular surface death receptors with their
successive ligands and the intrinsic pathway is dependent on the leakage of
cytochrome c from the mitochondria, which is prompted from the change or loss
of mitochondrial membrane potential. Triggering either of these pathways leads
to a downstream activation of a cascade of caspase proteolysis reactions. The
initiator caspase group includes caspase-8 and caspase-10 for the extrinsic
pathway and caspase-2 and caspase-9 for the intrinsic pathway. These caspases
bind to adapter molecules forming a death-inducing signaling complex (DISC).
Once the DISC is formed and the initiator caspases have been activated, they in
turn activate a series of downstream caspases known as effector caspases
(caspase-3, 6, 7) which are similar for both pathways. These effector caspases
subsequently cleave numerous structural and regulatory proteins leading to
apoptosis of the cell (Liu et al, 1997; Budihardjo et al, 1999). With such
involved pathways, cancer cells have evolved to resist apoptosis by many
mechanisms such as downregulating death receptor expression and overexpressing
inhibitors of apoptosis.
A. Death
receptors and tumor resistance
Like chemotherapy and irradiation, immune effector
cells (both T and NK cells) kill targets by activating apoptosis. This is
achieved by either releasing perforin and granzyme B, which activate caspases
directly, or by expressing or releasing death receptor ligands that interact
with death receptors on the surface of the target cells. The death receptor
pathway is an important aspect of perforin-independent cytotoxicity. Death
receptors are a subgroup of TNF-receptor family members that can trigger
caspase-8 activation and apoptosis upon interaction with their respective
ligands. Eight human death receptors - Fas (CD95), TNF-R1, TRAMP
(WSL-1/Apo-3/DR3/LARD), TRAIL-R1 (DR-4), TRAIL-R2 (DR-5), DR-6, EDA-R and NGF-R
- have been identified to date (Ashkenazi and Dixit, 1998, 1999). All are type
I membrane proteins containing two-four cysteine-rich extracellular domains and
a cytoplasmic "death domain". This cytoplasmic death domain couples
to receptors to trigger the caspase casade to induce apoptosis. Tumor cells,
however, have numerous mechanisms to resist this apoptosis driven pathway by
altering expression of these receptors or their downstream effector molecules.
One of the death receptors, Fas (CD95), and its
ligand, both critically involved in immune homeostasis and effector function,
are also the major pathway of cytolytic T-cell -mediated immunity involved in
specific killing of tumor cells. It has been well described that many different
tumor cells downregulate or lose of Fas expression on their surface (Shin et
al, 1999) {Lee, 2000 #37}. Bullani and colleagues, 2002 demonstrated the
reduction in Fas expression and/or death signaling function in atypical or
malignant melanocytic lesions as well as melanoma cell lines. Von Reyher and
colleagues determined that Fas is expressed in every colonocyte of normal colon
mucosa, but it is downregulated or lost in the majority of colon carcinomas
(von Reyher et al, 1998). Hughes and colleagues demonstrated that 69.5% of
esophageal adenocarcinomas evaluated were negative for Fas (Hughes et al,
1997).
We are now starting to develop a better understanding
to the mechanisms of escape to Fas or TRAIL receptor engagement. A mutant p53
gain of function has been shown to repress Fas gene expression (Zalcenstein et
al, 2003). Many tumor cells have been described to overexpress or
constitutively express Fas which, in turn, downregulates Fas expression.
Defects in the Fas-signaling pathway have also been described. The cellular
FLICE/caspase-8-inhibitory protein (cFLIP) can interfere with Fas-mediated cell
death and therefore favor tumor immune escape (French and Tschopp, 2002). cFLIP
has been reported to be constitutively expressed in all human HCC cell lines,
more so than in normal non-tumor liver tissues (Okano et al, 2003). cFLIP
expression was undetectable in all but one benign melanocytic lesion (31/32,
97%). In contrast, cFLIP was strongly expressed in most melanomas (24/29 =
83%). Overexpression of cFLIP by transfection in a Fas- and TRAIL-sensitive
human melanoma cell line rendered this cell line more resistant to death
mediated by both TRAIL and FasL. Selective expression of FLIP by human
melanomas may confer in vivo
resistance to FasL and TRAIL, thus representing an additional mechanism by
which melanoma cells escape immune destruction (Bullani et al, 2001).
Furthermore, loss of FADD protein expression, as well as loss of caspase 8
expression, is a means for tumor resistance to the death-receptor induced
apoptosis pathway (Teitz et al, 2000; Tourneur et al, 2003).
B.
Antiapotosis signaling molecules/inhibitors of apoptosis
Many antiapoptotic molecules are involved in the
resistance of tumor cells to apoptosis. Inhibitor of apoptosis proteins (IAPs)
consist of at least six family members (Deveraux and Reed, 1999; Deveraux et
al, 1999) IAP1,2, XIAP, ML-IAP (Vucic et al, 2000), Livin (Kasof and Gomes,
2001), Bruce and Surivin (Verhagen et al, 2001). XIAP is widely distributed
throughout the cytosol in both normal and cancer cells and inhibit caspase-3, 6
and 7. IAP1 and 2 interact with TNF-receptor associated factors (TRAFs) in the
membrane and perinuclear areas to inhibit caspase-3 and 7 (Verhagen et al,
2001). ML-IAP inhibits caspase-3, 7 and 9 in the nucleus and filamentous
structures in the cytoplasm (Vucic et al, 2000).
There are molecules that inhibit the binding of IAPs
to caspases. These proteins are released from the mitochondria into the cytosol
during changes of mitochondrial membrane potential permeability (Verhagen et
al, 2000). They are known as second mitocondria derived activator of caspases
(Smac/Diablo) and are located in the intermembrane space of the mitochondria.
They compete for binding sites on XIAPs thus releasing caspase 3,7 and 9. Omi
is another protein released from the mitochondria which binds to IAP and
facilitates apoptosis by freeing caspase 3 and 7 (Hedge and Williams, 2002).
Members of the B-cell lymphoma-2 (Bcl-2) protein
family have important roles in the regulation of cellular apoptosis for which
they elicit anti- or proapoptotic functions. Bcl-2, BclXl, Mcl-1, Bcl-w,
Bfl-1/a1, Bcl-b and Bcl-2-L-10 are antiapoptotic molecules whereas Bax, Bak,
Bad, Bid, Bcl-Xs, Mcl-1S, Bok/Mtd and Bik/Nbk are pro-apoptotic. There is a
general understanding that the pro-apoptotic molecules bind and neutralize
antiapoptotic molecules (Cheng et al, 2001) thus allowing apoptosis. Many
cancers, both solid and hematogenous, demonstrate an overexpression of Bcl-2
such as melanoma (Vlaykova et al, 2002), breast (Silvestrini et al, 1994; Wu et
al, 2000), prostate (McDonnell et al, 1992; Colombel et al, 1993), small cell
lung carcinoma (Jiang et al, 1995; Dingemans et al, 1999), colorectal carcinoma
(Sinicrope et al, 1996; Ilyas et al, 1998), transitional cell carcinoma
(Pollack et al, 1997) and solitary fibrous tumors (Hasegawa et al, 1998). This
overexpression of Bcl-2 correlates with worse prognosis. High levels of Bcl-Xl
were detected in bladder transitional cell carcinoma (Kirsh et al, 1998),
squamous cell cancer of the oropharynx, (Aebersold et al, 2001) and pancreatic
cancer. These molecules also contribute to tumor initiation, progression and
resistance to therapy and additionally associated with a worse prognosis
(Friess et al, 1998; Amundson et al, 2000).
The pro-apoptotic molecules, Bax and Bak, are required
in order to achieve apoptosis (Wei et al, 2001). Both Bax and Bak exist in
inactive conformations and are activated in response to various apoptotic
stimuli (Wolter et al, 1997; Gross et al, 1998). Bax is located in the cytosol
and translocates to the outer mitochondrial membrane upon activation. Bak is
located in active and inactive forms on the outer mitochondrial membrane
(Griffiths et al, 1999). Once activated, both Bax and Bak form multimeric
complexes. Mouse embryo fibroblasts deficient for Bax and Bak were refractory
to apoptosis after induction by various agents causing cell and mitochondrial
stress (Wei et al, 2001). Apoptosis induced by chemotherapeutic agents are
dependent on Bax. (Bellosillo et al, 2002, Deng et al, 2002). Furthermore,
epithelial cancer cells lacking Bax were resistant to apoptosis (Theodorakis et
al, 2002).
C.
Regulation of apoptosis MEK/ERK pathway
The RAS-RAF-MEK-ERK (extracellular signal-regulated
protein kinase) -MAPK (mitogen-activated protein kinase) pathway regulates
several key growth factors, cytokines and proto-oncogenes to promote cell
growth and differentiation. RAS is mutated to an oncogenic form in about 15% of
human cancers leading to an overexpression or constitutive activation of this
pathway (Davies et al, 2002). This pathway regulates antiapoptotic molecules
like Bcl-2, Bcl-XL and Mcl-1 leading to MAPK-dependent tumor-specific survival
signals in cancer cells, especially pancreatic carcinoma cells (Boucher et al,
2000) and melanoma cells (Eisenmann et al, 2003).
D.
Regulation of apoptosis by the Akt/PkB pathway
Numerous studies have shown the relevance of the Akt
pathway in promoting cell survival. Akt is constitutively activated in many
carcinomas such as prostate, breast, ovary, lung and liver (Vivanco and
Sawyers, 2002). It is thought that the activation of Akt leads to downstream
inhibition of apotosis. It has been suggested that Akt inhibits TRAIL induced
apoptosis by blocking Bid cleavage (Kandasamy and Srivastava, 2002). Akt also
inhibited Fas-mediated apoptosis by reducing recruitment of caspase 8 to the
DISC, reduced activation of caspase 8 and Bid (Jones et al, 2002). In addition,
Akt activation was reported to up-regulate c-FLIP in numerous cancer cell lines
(Panka et al, 2001). The down-regulation of pro-apoptotic molecules and
upregulation of anti-apoptotic molecules mediated by Akt/PkB has been suggested
in several studies (Hayakawa et al, 2000).
V.
Immunosensitization
The increasing understanding of the pathways by which
tumor cells resist apoptosis, together with the development of specific
inhibitors for critical molecules responsible for tumor resistance, may
facilitate the reversal of tumor escape from the immune system (Frost et al,
2001; Ng and Bonavida 2002). Modern immune-stimulating interventions resulting
from a more detailed knowledge on how immune effector cells are activated and
regulated have resulted in unprecedented expansion of circulating
antigen-specific T cells. Dendritic cell-based vaccines, repeated peptide-based
immunizations, viral-vector-mediated genetic immunization and adoptive transfer
of activated antigen-specific T cells have the ability to expand tumor-antigen
specific T cells to levels similar to those able to protect from viral
infections. However, the magnitude of tumor-antigen-specific T cell expansion
has not been unequivocally correlated with clinical responses. Therefore, it is
likely that a limiting step is that target cells can escape from death signals
delivered by adequately activated T cells. The knowledge of how target cells
escape immune-cell-mediated killing provides several means of intervention to
revert sensitivity to the immune system.
A. Blocking
immune suppressive soluble factors
As we have described earlier, there are several
well-known immune suppressive soluble factors that are secreted by most tumor
cells. It has been the focus of many to block these factors to reverse the
immune suppression.
1. TGF-b
There has been evidence of suppressing or blocking
TGF-b signaling can suppress tumor progression making this
molecule an attractive target. There are several agents targeting TGF-b that are in early stages of development such as anti-
TGF-b antibodies, small molecule inhibitors of TGF-b, Smad inhibitors (downstream target of TGF-b) and antisense gene therapy. Stable transduction of
breast and glioma tumor cells with antisense TGF-b 1 and TGF-b 2 retroviruses restored their immunogenicity and induced partial
rejection of unmodified established tumors (Fakhrai et al, 1996; Dumont and
Arteaga, 2003). Reversal of NK inhibition induced by tumor inoculation in
athymic mice was noted after the use of TGF-b neutralizing antibodies (Arteaga et al, 1993). Furthermore, antisense oligonucleotides targeting TGF-b2 DNA or mRNA inhibited malignant mesothelioma growth in vitro and in vivo (Marzo et al, 1997) as well as inhibited hepatocellular
carcinoma growth in vivo and
increased CTL lytic activity twofold in
vitro (Maggard et al, 2001). Blocking TGF-b also improved dendritic cell vaccines in vivo after using a combined TGF-b gene transfer plus TGF-b neutralizing antibody in established TGF-b-secreting 4T1 mammary tumors. The combined therapy
with the dendritic cell vaccine resulted in tumor regression in 40% of
established tumors 135.
2. COX-2 and prostaglandins
COX-2 inhibitors have recently been intensively
evaluated for their ability to treat and prevent cancers. COX-2 inhibitors are
being used in combination with other anti-cancer drugs or irradiation to treat
solid tumors, and have shown efficacy as a single agent for the prevention of
colorectal cancer in patients with familial adenomatous polyposis (Xu, 2002).
It has been shown that by inhibiting COX-2 tumor expression either genetically
or pharmacologically, the immunosuppressive effects on dendritic cells can be
reversed and dendritic cell phenotype and function can be restored (Sharma et
al, 2003). COX-2 inhibition also reversed tumor-induced suppression of
macrophage function (Duff et al, 2003). COX-2 inhibitors also induce apoptosis
via activation of caspase-3, caspase-9 and cytochrome c release in tumor cells
expressing COX-2, and block cell cycle regardless of their COX-2 expression
(Maier et al, 2004). In vivo
treatment of established Lewis lung cancer tumors with COX-2 inhibitor reduced
tumor growth in C57BL/6 mice (Williams et al, 2000).
3. VEGF
VEGF has several immunosuppressive effects that
promote tumor growth and invasion. Blocking negative effects of VEGF on
dendritic cell maturation by a neutralizing antibody reverses the negative
effects on dendritic cells in vitro
(Gabrilovich et al, 1999). It was then subsequently shown that antibodies to
VEGF can enhance the efficacy of cancer immunotherapy by improving dendritic
cell function in vivo. In this study,
tumor growth in mice was delayed and survival was prolonged by the addition of
VEGF antibody to a p53 peptide pulsed vaccine (Gabrilovich et al, 1999).
B. Re-expression of tumor antigens
DNA methylation is known to be an important mechanism
of gene regulation. It has also been noted to control tumor antigen expression
and lead to gene silencing 141. Demethylation of tumor antigen promotors responsible
for gene silencing can lead to a reactivation of their expression thus
increasing the sensitivity of tumor cells to immune surveillance. This can be
achieved by two classes of drugs, demethylating agents and histone deacetylase
inhibitors (HDACi). The MAGE genes (also known as cancer testis antigens),
expressed not only in melanomas but also in many other tumors, are activated by
promoter demethylation (De Smet et al, 1996; Coral et al, 1999). Furthermore,
the activation of MAGE expression on melanoma cells with 5-aza-2Õ-deoxycytidine
(DAC) elicits a MAGE-specific CTL response (Serrano et al, 2001). Other tumor
antigens, RAGE-1, GAGE 1-6 and NY-ESO-1, in renal cell carcinoma are also
regulated by DNA methylation and expression of these antigens can be induced by
DAC. In addition, de novo expression of NY-ESO-1 was noted in renal cell
carcinoma which elicited a NY-ESO-1 specific CTL-mediated lysis (Coral et al,
2002). In addition, these drugs have been shown to generate a pro-apoptotic
cell milieu by modulating the expression of several pro and anti-apoptotic
genes (Egger et al, 2004). The use of demethylating agents as an adjunct to
immunotherapy may be a possibility to enhance MHC expression of tumor antigens
and increase immune recognition and subsequent destruction of tumor cells.
C.
Interference with anti-apoptotic molecules
Because of the up-regulation of anti-apoptotic
molecules is a frequent observation in cancer cells, specific therapy to target
anti-apoptotic molecules may potentially immunosensitize tumor cells by
increasing their ability to undergo apoptosis. Many of these specific therapies
are currently in clinical trials, including an antisense to Bcl-2 construct
(G3139). A Bcl-2 inhibitor, ABT-737 was designed to be a potent inhibitor of
anti-apoptotic proteins Bcl-2, Bcl-Xl and BCL-w and has been shown to enhance
the effects of death signals and display synergistic toxiticities with
chemotherapies and radiation. As a single agent, it was therapeutic in the
cytotoxicity to lymphoma and small-cell lung carcinoma cell lines in both
patient derived cells and in animal models (Oltersdorf et al, 2005).
New molecules have been studied to specifically
disrupt the MAPK cascade leading to an overall decrease in activity of the
Bcl-2 family of anti-apoptotic molecules. Antitumor activity has been seen in
preclinical models with CI-1040, an orally active inhibitor of MEK1/2, for
pancreas colon, breast cancer (Allen et al, 2003) and melanoma (Collisson et
al, 2003). In addition ERK inhibitors PD98059 and U0126, when used in
conjunction with docetaxel, increased apoptosis and inactivated Bcl-2 in human
prostate cancer cells (Zelivianski et al, 2003).
The
use of XIAP antagonists have recently demonstrated efficacy in inducing
apoptosis in cancer cells on top of sensitizing cancer cells to chemotherapy (Yang et al, 2003). XIAP
antagonists have been designed creating a SMAC peptide complexed with the BIR3
domain of XIAP, which bind to the BIR3 domian of XIAP and promote cell death in
several human cancer cell lines and has inhibited growth of tumors in a
xenograft breast cancer model in mice (Oost et al, 2004). Additionally, new classes of
polyphenylureas with XIAP-inhibitory activity have been shown to overcome XIAP
mediated suppression of caspase 3 and 7, stimulate increased caspase activity
and directly induced apoptosis in many types of tumor cell lines in culture.
These polyphenylurea compounds also suppressed growth of established tumors in
xeongraft models in mice and sensitized cancer cells to chemotherapeutic drugs
(Schimmer et al, 2004).
D.
Enhancement of pro-apoptotic receptors and molecule expression
Anti-apoptotic family members heterodimerize with
pro-apoptotic family members and antagonize their function to resist cell
death. Synthetic peptide sequences derived from the BH3 domain of pro-apoptotic
Bcl-2 family members such as Bax and Bak have recently been generated to block
this heterodimerization thus allowing apoptosis. The usage of these synthetic
peptides increased apoptosis by 40% in prostate cells (Finnegan et al, 2001).
The use of an inducible recombinant Bax adenovirus was effective in enhancing
apoptotic cell death in both ovarian cancer cell lines and patient-derived
primary cancer cells and may provide a means to overcome the heterogeneous
nature of tumors (Xiang et al, 2000).
A small molecule mimic of Smac, a pro-apoptotic
protein that functions by relieving the IAP-mediated suppression of caspase
activity, has been synthesized to overcome IAP antagonist. This molecule also
synergizes with both TNF-a and TRAIL and is a
potential new therapy for cancer (Li et al, 2004).
VI.
Conclusions
In the past decade we have developed
a remarkable appreciation of the adaptive immunity and its role in detecting
cancer cells and impairing cancer growth, which have lead to numerous
immunotherapy trials. However, our immunotherapy strategies have not clinically
demonstrated effective control over tumor growth. We are now trying to focus
our attention on comprehending the potential reasons for failure by
understanding both the cellular and molecular pathways that interfere with the
immune systemÕs own ability to develop powerful immunologic responses against
the tumor cells. By exploring this knowledge of how tumor cells escape immune
surveillance and resist immune-mediated killing, we may be able to target
therapy and recreate an immune ÒsensitiveÓ environment. With the advent of many
newly developed small molecules inhibitors and specific antibodies it may be
possible to direct our therapy to specific apoptosis pathways and reverse
immune resistance, becoming an effective adjuvant to immunotherapy.
References
Aebersold DM, Burri P, Beer
KT, Laissue J, Djonov V, Greiner RH, Semenza GL (2001) Expression of hypoxia-inducible factor-1a: a novel predictive and
prognostic parameter in the radiotherapy of oropharyngeal cancer. Cancer Res 61, 2911-6.
Algarra I, Cabrera T, Garrido
F (2000) The HLA crossroad in tumor
immunology. Hum Immunol 61, 65-73.
Algarra I, Collado A, Garrido
F (1997) Altered MHC class I
antigens in tumors. Int J Clin Lab Res 27,
95-102.
Allen LF, Sebolt-Leopold J,
Meyer MB (2003) CI-1040 (PD184352),
a targeted signal transduction inhibitor of MEK (MAPKK). Semin Oncol 30, 105-16.
Amundson SA, Myers TG,
Scudiero D, Kitada S, Reed JC, Fornace AJ Jr (2000) An informatics approach identifying markers of chemosensitivity
in human cancer cell lines. Cancer Res 60,
6101-10.
Arteaga CL, Hurd SD, Winnier
AR, Johnson MD, Fendly BM, Forbes JT (1993)
Anti-transforming growth factor (TGF)-b antibodies inhibit breast
cancer cell tumorigenicity and increase mouse spleen natural killer cell
activity. Implications for a possible role of tumor cell/host TGF-b interactions in human breast
cancer progression. J Clin Invest 92,
2569-76.
Ashkenazi A, Dixit VM (1998) Death receptors: signaling and
modulation. Science 281, 1305-8.
Ashkenazi A, Dixit VM (1999) Apoptosis control by death and
decoy receptors. Curr Opin Cell Biol 11,
255-60.
Bellosillo B,
Villamor N, Lopez-Guillermo A, Marce S, Bosch F, Campo E, Montserrat E, Colomer
D (2002) Spontaneous and
drug-induced apoptosis is mediated by conformational changes of Bax and Bak in
B-cell chronic lymphocytic leukemia. Blood
100, 1810-6.
Benitez R, Godelaine D,
Lopez-Nevot MA, Brasseur F, Jimenez P, Marchand M, Oliva MR, van Baren N,
Cabrera T, Andry G, Landry C, Ruiz-Cabello F, Boon T, Garrido F (1998) Mutations of the b2-microglobulin gene result
in a lack of HLA class I molecules on melanoma cells of two patients immunized
with MAGE peptides. Tissue Antigens 52,
520-9.
Boon T, Cerottini JC, Van den
Eynde B, van der Bruggen P, Van Pel A (1994)
Tumor antigens recognized by T lymphocytes. Annu Rev Immunol 12, 337-65.
Boucher MJ, Morisset J,
Vachon PH, Reed JC, Laine J, Rivard N (2000)
MEK/ERK signaling pathway regulates the expression of Bcl-2, Bcl-X(L), and
Mcl-1 and promotes survival of human pancreatic cancer cells. J Cell Biochem 79, 355-69.
Browning M, Petronzelli F,
Bicknell D, et Browning M, Petronzelli F, Bicknell D, Krausa P, Rowan A, Tonks
S, Murray N, Bodmer J, Bodmer W.47, 364-71.
Budihardjo I, Oliver H,
Lutter M, Luo X, Wang X (1999)
Biochemical pathways of caspase activation during apoptosis. Annu Rev Cell Dev Biol 15, 269-90.
Bullani RR, Huard B,
Viard-Leveugle I, Byers HR, Irmler M, Saurat JH, Tschopp J, French LE (2001) Selective expression of FLIP in
malignant melanocytic skin lesions. J
Invest Dermatol 117, 360-4.
Bullani RR, Wehrli P,
Viard-Leveugle I, Rimoldi D, Cerottini JC, Saurat JH, Tschopp J, French LE (2002) Frequent downregulation of Fas
(CD95) expression and function in melanoma. Melanoma Res 12, 263-70.
Campoli M, Chang CC, Ferrone
S (2002) HLA class I antigen loss,
tumor immune escape and immune selection. Vaccine
20(suppl4), A40-5.
Chen CH, Seguin-Devaux C,
Burke NA, Oriss TB, Watkins SC, Clipstone N, Ray A (2003) Transforming growth factor b blocks Tec kinase phosphorylation,
Ca2+ influx, and NFATc translocation causing inhibition of T cell
differentiation. J Exp Med 197,
1689-99.
Cheng EH, Wei MC, Weiler S,
Flavell RA, Mak TW, Lindsten T, Korsmeyer SJ (2001) BCL-2, BCL-XL sequester BH3 domain-only molecules
preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol Cell 8, 705-11.
Collisson EA, De A, Suzuki H,
Gambhir SS, Kolodney MS (2003)
Treatment of metastatic melanoma with an orally available inhibitor of the
Ras-Raf-MAPK cascade. Cancer Res 63,
5669-73.
Colombel M, Symmans F, Gil S,
O'Toole KM, Chopin D, Benson M, Olsson CA, Korsmeyer S, Buttyan R (1993) Detection of the
apoptosis-suppressing oncoprotein bc1-2 in hormone-refractory human prostate
cancers. Am J Pathol 143, 390-400.
Coral S, Sigalotti L, Altomonte
M, Engelsberg A, Colizzi F, Cattarossi I, Maraskovsky E, Jager E, Seliger B,
Maio M (2002)
5-aza-2'-deoxycytidine-induced expression of functional cancer testis antigens
in human renal cell carcinoma: immunotherapeutic implications. Clin Cancer Res 8, 2690-5.
Coral S, Sigalotti L,
Gasparollo A, Cattarossi I, Visintin A, Cattelan A, Altomonte M, Maio M (1999) Prolonged upregulation of the
expression of HLA class I antigens and costimulatory molecules on melanoma
cells treated with 5-aza-2'-deoxycytidine (5-AZA-CdR). J Immunother 22, 16-24.
Cromme FV, Airey J, Heemels
MT, Ploegh HL, Keating PJ, Stern PL, Meijer CJ, Walboomers JM (1994) Loss of transporter protein,
encoded by the TAP-1 gene, is highly correlated with loss of HLA expression in
cervical carcinomas. J Exp Med 179,
335-40.
Davies H, Bignell GR, Cox C,
Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W,
Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou
V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R,
Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K,
Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A,
Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow
TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA (2002) Mutations of the BRAF gene in
human cancer. Nature 417, 949-54.
De Smet C, De Backer O,
Faraoni I, et al (1996) The
activation of human gene MAGE-1 in tumor cells is correlated with genome-wide
demethylation. Proc Natl Acad Sci USA 93,
7149-53.
Deng Y, Lin Y, Wu X (2002) TRAIL-induced apoptosis requires
Bax-dependent mitochondrial release of Smac/DIABLO. Genes Dev 16, 33-45.
Deveraux QL, Reed JC (1999) IAP family proteins--suppressors
of apoptosis. Genes Dev 13, 239-52.
Deveraux QL, Stennicke HR,
Salvesen GS, Reed JC (1999)
Endogenous inhibitors of caspases. J
Clin Immunol 19, 388-98.
Diefenbach A, Raulet DH (2002) The innate immune response to
tumors and its role in the induction of T-cell immunity. Immunol Rev 188, 9-21.
Dikov MM, Oyama T, Cheng P,
Takahashi T, Takahashi K, Sepetavec T, Edwards B, Adachi Y, Nadaf S, Daniel T,
Gabrilovich DI, Carbone DP (2001)
Vascular endothelial growth factor effects on nuclear factor-kappaB activation
in hematopoietic progenitor cells. Cancer
Res 61, 2015-21.
Dingemans AM, Witlox MA,
Stallaert RA, van der Valk P, Postmus PE, Giaccone G (1999) Expression of DNA topoisomerase IIa and topoisomerase IIb genes predicts survival and
response to chemotherapy in patients with small cell lung cancer. Clin Cancer Res 5, 2048-58.
Dissemond J, Kothen T, Mors
J, Weimann TK, Lindeke A, Goos M, Wagner SN (2003) Downregulation of tapasin expression in progressive human
malignant melanoma. Arch Dermatol Res 295,
43-9.
Dohadwala M, Luo J, Zhu L,
Lin Y, Dougherty GJ, Sharma S, Huang M, Pold M, Batra RK, Dubinett SM (2001) Non-small cell lung cancer
cyclooxygenase-2-dependent invasion is mediated by CD44. J Biol Chem 276, 20809-12.
Doubrovina ES, Doubrovin MM,
Vider E, Sisson RB, O'Reilly RJ, Dupont B, Vyas YM (2003) Evasion from NK cell immunity by MHC class I chain-related
molecules expressing colon adenocarcinoma. J
Immunol 171, 6891-9.
Duff M, Stapleton PP, Mestre
JR, Maddali S, Smyth GP, Yan Z, Freeman TA, Daly JM (2003) Cyclooxygenase-2 inhibition improves macrophage function in
melanoma and increases the antineoplastic activity of interferon g. Ann Surg Oncol 10, 305-13.
Dumont N, Arteaga CL (2003) Targeting the TGFb signaling network in human neoplasia.
Cancer Cell 3, 531-6.
Dunn GP, Bruce AT, Ikeda H,
Old LJ, Schreiber RD (2002) Cancer
immunoediting: from immunosurveillance to tumor escape. Nat Immunol 3, 991-8.
D'Urso CM, Wang ZG, Cao Y,
Tatake R, Zeff RA, Ferrone S (1991)
Lack of HLA class I antigen expression by cultured melanoma cells FO-1 due to a
defect in B2m gene expression. J Clin
Invest 87, 284-92.
Ebert O, Ropke G, Marten A,
Lefterova P, Micka B, Buttgereit P, Niemitz S, Trojaneck B, Schmidt-Wolf G,
Huhn D, Wittig B, Schmidt-Wolf IG (1999)
TNF-a secretion and apoptosis of lymphocytes mediated by
gene transfer. Cytokines Cell Mol Ther 5,
165-73.
Egger G, Liang G, Aparicio A,
Jones PA (2004) Epigenetics in human
disease and prospects for epigenetic therapy. Nature 429, 457-63.
Eisenmann KM, VanBrocklin MW,
Staffend NA, Kitchen SM, Koo HM (2003)
Mitogen-activated protein kinase pathway-dependent tumor-specific survival
signaling in melanoma cells through inactivation of the proapoptotic protein
bad. Cancer Res 63, 8330-7.
Fakhrai H, Dorigo O, Shawler
DL, Lin H, Mercola D, Black KL, Royston I, Sobol RE (1996) Eradication of established intracranial rat gliomas by
transforming growth factor b antisense gene therapy. Proc Natl Acad Sci USA 93, 2909-14.
Ferrara N (1996) Vascular endothelial growth
factor. Eur J Cancer 32A:, 2413-22.
Finnegan NM, Curtin JF,
Prevost G, Morgan B, Cotter TG (2001)
Induction of apoptosis in prostate carcinoma cells by BH3 peptides which
inhibit Bak/Bcl-2 interactions. Br J
Cancer 85, 115-21.
Franksson L, George E, Powis
S, Butcher G, Howard J, Karre K (1993)
Tumorigenicity conferred to lymphoma mutant by major histocompatibility
complex-encoded transporter gene. J Exp
Med 177, 201-5.
French LE, Tschopp J (2002) Defective death receptor
signaling as a cause of tumor immune escape. Semin Cancer Biol 12, 51-5.
Friess H, Lu Z,
Andren-Sandberg A, Berberat P, Zimmermann A, Adler G, Schmid R, Buchler MW (1998) Moderate activation of the
apoptosis inhibitor bcl-xL worsens the prognosis in pancreatic cancer. Ann Surg 228, 780-7.
Frost PJ, Butterfield LH,
Dissette VB, Economou JS, Bonavida B (2001)
Immunosensitization of melanoma tumor cells to non-MHC Fas-mediated killing by
MART-1-specific CTL cultures. J Immunol 166,
3564-73.
Gabrilovich D, Ishida T,
Oyama T, Ran S, Kravtsov V, Nadaf S, Carbone DP (1998) Vascular endothelial growth factor inhibits the development
of dendritic cells and dramatically affects the differentiation of multiple
hematopoietic lineages in vivo. Blood 92,
4150-66.
Gabrilovich DI, Ishida T,
Nadaf S, Ohm JE, Carbone DP (1999)
Antibodies to vascular endothelial growth factor enhance the efficacy of cancer
immunotherapy by improving endogenous dendritic cell function. Clin Cancer Res 5, 2963-70.
Garcia-Lora A, Martinez M,
Algarra I, Gaforio JJ, Garrido F (2003)
MHC class I-deficient metastatic tumor variants immunoselected by T lymphocytes
originate from the coordinated downregulation of APM components. Int J Cancer 106, 521-7.
Garrido F, Cabrera T, Concha
A, Glew S, Ruiz-Cabello F, Stern PL (1993)
Natural history of HLA expression during tumour development. Immunol Today 14, 491-9.
Garrido F, Ruiz-Cabello F,
Cabrera T, Perez-Villar JJ, Lopez-Botet M, Duggan-Keen M, Stern PL (1997) Implications for
immunosurveillance of altered HLA class I phenotypes in human tumours. Immunol Today 18, 89-95.
Gastl GA, Abrams JS, Nanus
DM, Oosterkamp R, Silver J, Liu F, Chen M, Albino AP, Bander NH (1993) Interleukin-10 production by
human carcinoma cell lines and its relationship to interleukin-6 expression. Int J Cancer 55, 96-101.
Geiss Geissmann F, Revy P,
Regnault A, Lepelletier Y, Dy M, Brousse N, Amigorena S, Hermine O, Durandy A (1999) TGF-b 1 prevents the noncognate
maturation of human dendritic Langerhans cells. J Immunol 162, 4567-75.
Gray JD, Hirokawa M, Horwitz
DA (1994) The role of transforming
growth factor b in the generation of suppression: an
interaction between CD8+ T and NK cells. J
Exp Med 180, 1937-42.
Gray JD, Hirokawa M, Ohtsuka
K, Horwitz DA (1998) Generation of
an inhibitory circuit involving CD8+ T cells, IL-2, and NK cell-derived TGF-b: contrasting effects of
anti-CD2 and anti-CD3. J Immunol 160,
2248-54.
Griffiths GJ, Dubrez L,
Morgan CP, Jones NA, Whitehouse J, Corfe BM, Dive C, Hickman JA (1999) Cell damage-induced
conformational changes of the pro-apoptotic protein Bak in vivo precede the
onset of apoptosis. J Cell Biol 144,
903-14.
Groh V, Wu J, Yee C, Spies T
(2002) Tumour-derived soluble MIC
ligands impair expression of NKG2D and T-cell activation. Nature 419, 734-8.
Gross A, Jockel J, Wei MC,
Korsmeyer SJ (1998) Enforced
dimerization of BAX results in its translocation, mitochondrial dysfunction and
apoptosis. Embo J 17, 3878-85.
Hasegawa T, Matsuno Y,
Shimoda T, Hirohashi S, Hirose T, Sano T (1998)
Frequent expression of bcl-2 protein in solitary fibrous tumors. Jpn J Clin Oncol 28, 86-91.
Hayakawa J, Ohmichi M,
Kurachi H, Kanda Y, Hisamoto K, Nishio Y, Adachi K, Tasaka K, Kanzaki T, Murata
Y (2000) Inhibition of BAD
phosphorylation either at serine 112 via extracellular signal-regulated protein
kinase cascade or at serine 136 via Akt cascade sensitizes human ovarian cancer
cells to cisplatin. Cancer Res 60,
5988-94.
Hedge VL, Williams GT (2002) Commitment to apoptosis induced
by tumour necrosis factor-a is dependent on caspase
activity. Apoptosis 7, 123-32.
Herschman HR (1996) Prostaglandin synthase 2. Biochim Biophys Acta 1299, 125-40.
Hicklin DJ, Marincola FM,
Ferrone S (1999) HLA class I antigen
downregulation in human cancers: T-cell immunotherapy revives an old story. Mol Med Today 5, 178-86.
Hickman JA (2002) Apoptosis and tumourigenesis. Curr Opin Genet Dev 12, 67-72.
Huang M, Wang J, Lee P,
Sharma S, Mao JT, Meissner H, Uyemura K, Modlin R, Wollman J, Dubinett SM (1995) Human non-small cell lung cancer
cells express a type 2 cytokine pattern. Cancer
Res 55, 3847-53.
Hughes SJ, Nambu Y, Soldes
OS, Hamstra D, Rehemtulla A, Iannettoni MD, Orringer MB, Beer DG (1997) Fas/APO-1 (CD95) is not
translocated to the cell membrane in esophageal adenocarcinoma. Cancer Res 57, 5571-8.
Ilyas M, Hao XP, Wilkinson K,
Tomlinson IP, Abbasi AM, Forbes A, Bodmer WF, Talbot IC (1998) Loss of Bcl-2 expression correlates with tumour recurrence in
colorectal cancer. Gut 43, 383-7.
Jiang SX, Sato Y, Kuwao S,
Kameya T (1995) Expression of bcl-2
oncogene protein is prevalent in small cell lung carcinomas. J Pathol 177, 135-8.
Johnsen AK, Templeton DJ, Sy
M, Harding CV (1999) Deficiency of
transporter for antigen presentation (TAP) in tumor cells allows evasion of
immune surveillance and increases tumorigenesis. J Immunol 163, 4224-31.
Jones RG, Elford AR, Parsons
MJ, Wu L, Krawczyk CM, Yeh WC, Hakem R, Rottapel R, Woodgett JR, Ohashi PS (2002) CD28-dependent activation of
protein kinase B/Akt blocks Fas-mediated apoptosis by preventing death-inducing
signaling complex assembly. J Exp Med 196,
335-48.
Kageshita T, Hirai S, Ono T,
Hicklin DJ, Ferrone S (1999)
Down-regulation of HLA class I antigen-processing molecules in malignant
melanoma: association with disease progression. Am J Pathol 154, 745-54.
Kandasamy K, Srivastava RK (2002) Role of the phosphatidylinositol
3'-kinase/PTEN/Akt kinase pathway in tumor necrosis factor-related
apoptosis-inducing ligand-induced apoptosis in non-small cell lung cancer
cells. Cancer Res 62, 4929-37.
Kao JY, Gong Y, Chen CM,
Zheng QD, Chen JJ (2003)
Tumor-derived TGF-b reduces the efficacy of dendritic cell/tumor
fusion vaccine. J Immunol 170,
3806-11.
Karre K (2002) NK cells, MHC class I molecules and the missing self. Scand J Immunol 55, 221-8.
Kasof GM, Gomes BC (2001) Livin, a novel inhibitor of
apoptosis protein family member. J Biol
Chem 276, 3238-46.
Keating PJ, Cromme FV,
Duggan-Keen M, Snijders PJ, Walboomers JM, Hunter RD, Dyer PA, Stern PL (1995) Frequency of down-regulation of
individual HLA-A and -B alleles in cervical carcinomas in relation to TAP-1
expression. Br J Cancer 72, 405-11.
Kim CJ, Prevette T, Cormier
J, Overwijk W, Roden M, Restifo NP, Rosenberg SA, Marincola FM (1997) Dendritic cells infected with
poxviruses encoding MART-1/Melan A sensitize T lymphocytes in vitro. J Immunother 20, 276-86.
Kirsh EJ, Baunoch DA, Stadler
WM (1998) Expression of bcl-2 and
bcl-X in bladder cancer. J Urol 159,
1348-53.
Kobie JJ, Wu RS, Kurt RA, Lou
S, Adelman MK, Whitesell LJ, Ramanathapuram LV, Arteaga CL, Akporiaye ET (2003) Transforming growth factor b inhibits the
antigen-presenting functions and antitumor activity of dendritic cell vaccines.
Cancer Res 63, 1860-4.
LaCasse EC, Baird S, Korneluk
RG, MacKenzie AE (1998) The
inhibitors of apoptosis (IAPs) and their emerging role in cancer. Oncogene 17, 3247-59.
Lanier LL (2003) Natural killer cell receptor
signaling. Curr Opin Immunol 15,
308-14.
Leahy KM, Koki AT, Masferrer
JL (2000) Role of cyclooxygenases in
angiogenesis. Curr Med Chem 7,
1163-70.
Li L, Thomas
RM, Suzuki H, De Brabander JK, Wang X, Harran PG (2004) A small molecule Smac mimic potentiates TRAIL- and TNFa-mediated cell death. Science 305, 1471-4.
Liu X, Zou H, Slaughter C,
Wang X (1997) DFF, a heterodimeric
protein that functions downstream of caspase-3 to trigger DNA fragmentation
during apoptosis. Cell 89, 175-84.
Ljunggren HG, Karre K (1985) Host resistance directed
selectively against H-2-deficient lymphoma variants. Analysis of the mechanism.
J Exp Med 162, 1745-59.
Lopez-Botet M, Moretta L,
Strominger J (1996) NK-cell receptors
and recognition of MHC class I molecules. Immunol
Today 17, 212-4.
Maggard M, Meng L, Ke B,
Allen R, Devgan L, Imagawa DK (2001)
Antisense TGF-b2 immunotherapy for hepatocellular carcinoma:
treatment in a rat tumor model. Ann Surg
Oncol 8, 32-7.
Maier TJ, Schilling K,
Schmidt R, Geisslinger G, Grosch S (2004)
Cyclooxygenase-2 (COX-2)-dependent and -independent anticarcinogenic effects of
celecoxib in human colon carcinoma cells. Biochem
Pharmacol 67, 1469-78.
Marincola FM, Jaffee EM,
Hicklin DJ, Ferrone S (2000) Escape
of human solid tumors from T-cell recognition: molecular mechanisms and
functional significance. Adv Immunol 74,
181-273.
Marzo AL, Fitzpatrick DR,
Robinson BW, Scott B (1997)
Antisense oligonucleotides specific for transforming growth factor b2 inhibit the growth of
malignant mesothelioma both in vitro and in vivo. Cancer Res 57, 3200-7.
Matsuda M, Salazar F,
Petersson M, Masucci G, Hansson J, Pisa P, Zhang QJ, Masucci MG, Kiessling R (1994) Interleukin 10 pretreatment
protects target cells from tumor- and allo-specific cytotoxic T cells and
downregulates HLA class I expression. J
Exp Med 180, 2371-6.
McDonnell TJ, Troncoso P,
Brisbay SM, Logothetis C, Chung LW, Hsieh JT, Tu SM, Campbell ML (1992) Expression of the protooncogene
bcl-2 in the prostate and its association with emergence of
androgen-independent prostate cancer. Cancer
Res 52, 6940-4.
Moore KW, O'Garra A, de Waal
Malefyt R, Vieira P, Mosmann TR (1993)
Interleukin-10. Annu Rev Immunol 11,
165-90.
Moretta A, Vitale M, Sivori
S, Morelli L, Pende D, Bottino C (1996)
Inhibitory and activatory receptors for HLA class I molecules in human natural
killer cells. Chem Immunol 64,
77-87.
Neuner A, Schindel M,
Wildenberg U, Muley T, Lahm H, Fischer JR (2001)
Cytokine secretion: clinical relevance of immunosuppression in non-small cell
lung cancer. Lung Cancer 34(suppl2),
S79-82.
Ng CP, Bonavida B (2002) A new challenge for successful
immunotherapy by tumors that are resistant to apoptosis: two complementary
signals to overcome cross-resistance. Adv
Cancer Res 85, 145-74.
Ng CP, Bonavida B (2002) X-linked inhibitor of apoptosis
(XIAP) blocks Apo2 ligand/tumor necrosis factor-related apoptosis-inducing
ligand-mediated apoptosis of prostate cancer cells in the presence of
mitochondrial activation: sensitization by overexpression of second
mitochondria-derived activator of caspase/direct IAP-binding protein with low
pl (Smac/DIABLO). Mol Cancer Ther 1,
1051-8.
Ohm JE, Carbone DP (2002) Immune dysfunction in cancer
patients. Oncology (Williston Park) 16,
11-8.
Ohm JE, Gabrilovich DI,
Sempowski GD, Kisseleva E, Parman KS, Nadaf S, Carbone DP (2003) VEGF inhibits T-cell development and may contribute to
tumor-induced immune suppression. Blood 101,
4878-86.
Okano H, Shiraki K, Inoue H,
Kawakita T, Yamanaka T, Deguchi M, Sugimoto K, Sakai T, Ohmori S, Fujikawa K,
Murata K, Nakano T (2003) Cellular
FLICE/caspase-8-inhibitory protein as a principal regulator of cell death and
survival in human hepatocellular carcinoma. Lab Invest 83, 1033-43.
Oltersdorf T, Elmore SW,
Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, Bruncko M, Deckwerth TL,
Dinges J, Hajduk PJ, Joseph MK, Kitada S, Korsmeyer SJ, Kunzer AR, Letai A, Li
C, Mitten MJ, Nettesheim DG, Ng S, Nimmer PM, O'Connor JM, Oleksijew A, Petros
AM, Reed JC, Shen W, Tahir SK, Thompson CB, Tomaselli KJ, Wang B, Wendt MD,
Zhang H, Fesik SW, Rosenberg SH (2005)
An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435, 677-81.
Oost TK, Sun C, Armstrong RC,
Al-Assaad AS, Betz SF, Deckwerth TL, Ding H, Elmore SW, Meadows RP, Olejniczak
ET, Oleksijew A, Oltersdorf T, Rosenberg SH, Shoemaker AR, Tomaselli KJ, Zou H,
Fesik SW (2004) Discovery of potent
antagonists of the antiapoptotic protein XIAP for the treatment of cancer. J Med Chem 47, 4417-26.
Panka DJ, Mano T, Suhara T,
Walsh K, Mier JW (2001)
Phosphatidylinositol 3-kinase/Akt activity regulates c-FLIP expression in tumor
cells. J Biol Chem 276, 6893-6.
Perez B, Benitez R, Fernandez
MA, Oliva MR, Soto JL, Serrano S, Lopez Nevot MA, Garrido F (1999) A new b 2 microglobulin mutation
found in a melanoma tumor cell line. Tissue
Antigens 53, 569-72.
Piontek GE, Taniguchi K,
Ljunggren HG, Gronberg A, Kiessling R, Klein G, Karre K (1985) YAC-1 MHC class I variants reveal an association between
decreased NK sensitivity and increased H-2 expression after interferon
treatment or in vivo passage. J Immunol 135,
4281-8.
Pockaj BA, Basu GD, Pathangey
LB, Gray RJ, Hernandez JL, Gendler SJ, Mukherjee P (2004) Reduced T-cell and dendritic cell function is related to
cyclooxygenase-2 overexpression and prostaglandin E2 secretion in patients with
breast cancer. Ann Surg Oncol 11,
328-39.
Pollack A, Wu CS, Czerniak B,
Zagars GK, Benedict WF, McDonnell TJ (1997)
Abnormal bcl-2 and pRb expression are independent correlates of radiation
response in muscle-invasive bladder cancer. Clin Cancer Res 3, 1823-9.
Reed JC (1999) Dysregulation of apoptosis in cancer. J Clin Oncol 17, 2941-53.
Restifo NP, Marincola FM,
Kawakami Y, Taubenberger J, Yannelli JR, Rosenberg SA (1996) Loss of functional b2-microglobulin in metastatic
melanomas from five patients receiving immunotherapy. J Natl Cancer Inst 88, 100-8.
Rosenberg SA, Yang JC,
Restifo NP (2004) Cancer
immunotherapy: moving beyond current vaccines. Nat Med 10, 909-15.
Salazar-Onfray F, Charo J,
Petersson M, Freland S, Noffz G, Qin Z, Blankenstein T, Ljunggren HG, Kiessling
R (1997) Down-regulation of the
expression and function of the transporter associated with antigen processing
in murine tumor cell lines expressing IL-10. J Immunol 159, 3195-202.
Schimmer AD, Welsh K, Pinilla
C, Wang Z, Krajewska M, Bonneau MJ, Pedersen IM, Kitada S, Scott FL,
Bailly-Maitre B, Glinsky G, Scudiero D, Sausville E, Salvesen G, Nefzi A,
Ostresh JM, Houghten RA, Reed JC (2004)
Small-molecule antagonists of apoptosis suppressor XIAP exhibit broad antitumor
activity. Cancer Cell 5, 25-35.
Seliger B, Wollscheid U,
Momburg F, Blankenstein T, Huber C (2000)
Coordinate downregulation of multiple MHC class I antigen processing genes in
chemical-induced murine tumor cell lines of distinct origin. Tissue Antigens 56, 327-36.
Serrano A, Tanzarella S,
Lionello I, Mendez R, Traversari C, Ruiz-Cabello F, Garrido F (2001) Rexpression of HLA class I
antigens and restoration of antigen-specific CTL response in melanoma cells
following 5-aza-2'-deoxycytidine treatment. Int J Cancer 94, 243-51.
Shankaran V, Ikeda H, Bruce
AT, White JM, Swanson PE, Old LJ, Schreiber RD (2001) IFNg and lymphocytes prevent
primary tumour development and shape tumour immunogenicity. Nature 410, 1107-11.
Sharma S, Stolina M, Yang SC,
Baratelli F, Lin JF, Atianzar K, Luo J, Zhu L, Lin Y, Huang M, Dohadwala M,
Batra RK, Dubinett SM (2003) Tumor
cyclooxygenase 2-dependent suppression of dendritic cell function. Clin Cancer Res 9, 961-8.
Shin MS, Park WS, Kim SY, Kim
HS, Kang SJ, Song KY, Park JY, Dong SM, Pi JH, Oh RR, Lee JY, Yoo NJ, Lee SH (1999) Alterations of Fas (Apo-1/CD95)
gene in cutaneous malignant melanoma. Am
J Pathol 154, 1785-91.
Siegel PM, Massague J (2003) Cytostatic and apoptotic actions
of TGF-b in homeostasis and cancer. Nat Rev Cancer 3, 807-21.
Silvestrini R, Veneroni S,
Daidone MG, Benini E, Boracchi P, Mezzetti M, Di Fronzo G, Rilke F, Veronesi U
(1994) The Bcl-2 protein: a
prognostic indicator strongly related to p53 protein in lymph node-negative
breast cancer patients. J Natl Cancer
Inst 86, 499-504.
Sinicrope FA, Roddey G,
McDonnell TJ, Shen Y, Cleary KR, Stephens LC (1996) Increased apoptosis accompanies neoplastic development in the
human colorectum. Clin Cancer Res 2,
1999-2006.
Soslow RA, Dannenberg AJ,
Rush D, Woerner BM, Khan KN, Masferrer J, Koki AT (2000) COX-2 is expressed in human pulmonary, colonic, and mammary
tumors. Cancer 89, 2637-45.
Stolina M, Sharma S, Lin Y,
Dohadwala M, Gardner B, Luo J, Zhu L, Kronenberg M, Miller PW, Portanova J, Lee
JC, Dubinett SM (2000) Specific
inhibition of cyclooxygenase 2 restores antitumor reactivity by altering the
balance of IL-10 and IL-12 synthesis. J
Immunol 164, 361-70.
Tajima K, Matsumoto N, Ohmori
K, Wada H, Ito M, Suzuki K, Yamamoto K (2004)
Augmentation of NK cell-mediated cytotoxicity to tumor cells by inhibitory NK
cell receptor blockers. Int Immunol 16,
385-93.
Taniguchi K, Karre K, Klein G
(1985) Lung colonization and
metastasis by disseminated B16 melanoma cells: H-2 associated control at the
level of the host and the tumor cell. Int
J Cancer 36, 503-10.
Teitz T, Wei T, Valentine MB,
Vanin EF, Grenet J, Valentine VA, Behm FG, Look AT, Lahti JM, Kidd VJ (2000) Caspase 8 is deleted or silenced
preferentially in childhood neuroblastomas with amplification of MYCN. Nat Med 6, 529-35.
Theodorakis P, Lomonosova E,
Chinnadurai G (2002) Critical
requirement of BAX for manifestation of apoptosis induced by multiple stimuli
in human epithelial cancer cells. Cancer
Res 62, 3373-6.
Torres MJ, Ruiz-Cabello F,
Skoudy A, Berrozpe G, Jimenez P, Serrano A, Real FX, Garrido F (1996) Loss of an HLA haplotype in
pancreas cancer tissue and its corresponding tumor derived cell line. Tissue Antigens 47, 372-81.
Tourneur L, Mistou S,
Michiels FM, Devauchelle V, Renia L, Feunteun J, Chiocchia G (2003) Loss of FADD protein expression
results in a biased Fas-signaling pathway and correlates with the development
of tumoral status in thyroid follicular cells. Oncogene 22, 2795-804.
Trapani JA, Davis J, Sutton
VR, Smyth MJ (2000) Proapoptotic
functions of cytotoxic lymphocyte granule constituents in vitro and in vivo. Curr Opin Immunol 12, 323-9.
Tsujii M, DuBois RN (1995) Alterations in cellular adhesion
and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide
synthase 2. Cell 83, 493-501.
Tsuruma T, Yagihashi A,
Hirata K, Torigoe T, Araya J, Watanabe N, Sato N (1999) Interleukin-10 reduces natural killer (NK) sensitivity of
tumor cells by downregulating NK target structure expression. Cell Immunol 198, 103-10.
Verhagen AM, Coulson EJ, Vaux
DL (2001) Inhibitor of apoptosis
proteins and their relatives: IAPs and other BIRPs. Genome Biol 2, REVIEWS3009.
Verhagen AM, Ekert PG,
Pakusch M, Silke J, Connolly LM, Reid GE, Moritz RL, Simpson RJ, Vaux DL (2000) Identification of DIABLO, a
mammalian protein that promotes apoptosis by binding to and antagonizing IAP
proteins. Cell 102, 43-53.
Vitale M, Rezzani R, Rodella
L, Zauli G, Grigolato P, Cadei M, Hicklin DJ, Ferrone S (1998) HLA class I antigen and transporter associated with antigen
processing (TAP1 and TAP2) down-regulation in high-grade primary breast
carcinoma lesions. Cancer Res 58,
737-42.
Vivanco I, Sawyers CL (2002) The phosphatidylinositol 3-Kinase
AKT pathway in human cancer. Nat Rev
Cancer 2, 489-501.
Vlaykova T, Talve L,
Hahka-Kemppinen M, Hernberg M, Muhonen T, Collan Y, Pyrhonen S (2002) Immunohistochemically detectable
bcl-2 expression in metastatic melanoma: association with survival and
treatment response. Oncology 62,
259-68.
von Bernstorff W, Voss M,
Freichel S, Schmid A, Vogel I, Johnk C, Henne-Bruns D, Kremer B, Kalthoff H (2001) Systemic and local
immunosuppression in pancreatic cancer patients. Clin Cancer Res 7, 925s-932s.
von Reyher U, Strater J,
Kittstein W, et al (1998) Colon
carcinoma cells use different mechanisms to escape CD95-mediated apoptosis. Cancer Res 58, 526-34.
Vucic D, Stennicke HR,
Pisabarro MT, Salvesen GS, Dixit VM (2000)
ML-IAP, a novel inhibitor of apoptosis that is preferentially expressed in
human melanomas. Curr Biol 10,
1359-66.
Wahl SM, Swisher J,
McCartney-Francis N, Chen W (2004)
TGF-b: the perpetrator of immune suppression by
regulatory T cells and suicidal T cells. J
Leukoc Biol 76, 15-24.
Wang RF (2001) The role of MHC class II-restricted tumor antigens and CD4+ T
cells in antitumor immunity. Trends
Immunol 22, 269-76.
Wei MC, Zong WX, Cheng EH,
Lindsten T, Panoutsakopoulou V, Ross AJ, Roth KA, MacGregor GR, Thompson CB,
Korsmeyer SJ (2001) Proapoptotic BAX
and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292, 727-30.
Whiteside TL, Goldfarb RH (1994) Antitumor effector cells:
extravasation and control of metastasis. Immunol
Ser 61, 159-73.
Williams CS, Tsujii M, Reese
J, Dey SK, DuBois RN (2000) Host
cyclooxygenase-2 modulates carcinoma growth. J Clin Invest 105, 1589-94.
Wojtowicz-Praga S (2003) Reversal of tumor-induced
immunosuppression by TGF-b inhibitors. Invest New Drugs 21, 21-32.
Wolter KG, Hsu YT, Smith CL,
Nechushtan A, Xi XG, Youle RJ (1997)
Movement of Bax from the cytosol to mitochondria during apoptosis. J Cell Biol 139, 1281-92.
Wu J, Shao ZM, Shen ZZ, et al
(2000) Significance of Apoptosis and
Apoptotic-Related Proteins, Bcl-2, and Bax in Primary Breast Cancer. Breast J 6, 44-52.
Xiang J, Gomez-Navarro J,
Arafat W, Liu B, Barker SD, Alvarez RD, Siegal GP, Curiel DT (2000) Pro-apoptotic treatment with an
adenovirus encoding Bax enhances the effect of chemotherapy in ovarian cancer. J Gene Med 2, 97-106.
Xu XC (2002) COX-2 inhibitors in cancer treatment and prevention, a recent
development. Anticancer Drugs 13,
127-37.
Yang L, Cao Z, Yan H, Wood WC
(2003) Coexistence of high levels of
apoptotic signaling and inhibitor of apoptosis proteins in human tumor cells:
implication for cancer specific therapy. Cancer
Res 63, 6815-24.
Zalcenstein A, Weisz L,
Stambolsky P, Bar J, Rotter V, Oren M (2003)
Mutant p53 gain of function: repression of CD95(Fas/APO-1) gene expression by
tumor-associated p53 mutants. Oncogene 22,
5667-76.
Zelivianski S, Spellman M, Kellerman M, Kakitelashvilli V, Zhou XW, Lugo
E, Lee MS, Taylor R, Davis TL, Hauke R, Lin MF (2003) ERK inhibitor PD98059 enhances docetaxel-induced apoptosis of
androgen-independent human prostate cancer cells. Int J Cancer 107, 478-85.
