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Emerging Mechanisms of Immunosuppression in Oral Cancers

¹ The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, and Division of Oral Biology and Medicine, Jonsson Comprehensive Cancer Center (JCCC),
² Department of Head and Neck surgery, and
³ Department of Radiation Oncology, UCLA School of Dentistry and Medicine, 10833 Le Conte Ave., University of California, Los Angeles, CA 90095-1668, USA

Correspondence: ^* corresponding author, ajewett{at}ucla.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION MECHANISMS OF IMMUNOSUPPRESSION... IMMUNOSUPPRESSIVE FACTORS... IMMUNOSUPPRESSION MEDIATED BY... TARGETING TRANSCRIPTION FACTORS... DRUGS THAT TARGET TRANSCRIPTION... CONCLUSIONS REFERENCES

 
Mounting effective anti-tumor immune responses against tumors by both the innate and adaptive immune effectors is important for the clearance of tumors. However, accumulated evidence indicates that immune responses that should otherwise suppress or eliminate transformed cells are themselves suppressed by the function of tumor cells in a variety of cancer patients, including those with oral cancers. Signaling abnormalities, spontaneous apoptosis, and reduced proliferation and function of circulating natural killer cells (NK), T-cells, dendritic cells (DC), and tumor-infiltrating lymphocytes (TILs) have been documented previously in oral cancer patients. Several mechanisms have been proposed for the functional deficiencies of tumor-associated immune cells in oral cancer patients. Both soluble factors and contact-mediated immunosuppression by the tumor cells have been implicated in the inhibition of immune cell function and the progression of tumors. More recently, elevated levels and function of key transcription factors in tumor cells, particularly NFB and STAT3, have been shown to mediate immune suppression in the tumor microenvironment. This review will focus on these emerging mechanisms of immunosuppression in oral cancers.

Key Words: apoptosis • NFB • TNF- • IFN- • NK • IL-6 • MCP-1 • RANTES • oral cancer • immune suppression

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MECHANISMS OF IMMUNOSUPPRESSION... IMMUNOSUPPRESSIVE FACTORS... IMMUNOSUPPRESSION MEDIATED BY... TARGETING TRANSCRIPTION FACTORS... DRUGS THAT TARGET TRANSCRIPTION... CONCLUSIONS REFERENCES

 
There is ample evidence for the role of effective immune cell function in the prevention of cancer. Resolution of oral non-Hodgkin’s lymphoma in a renal allograft recipient was observed after the reduction of immunosuppressive therapy (Keogh et al., 2002). In a liver transplant recipient, rapid progression of oral leukoplakia to carcinoma was observed after immunosuppression (Hernandez et al., 2003). Furthermore, neoplasias of the tongue and lip have been widely described in renal transplant patients (King et al., 1995; de Visscher et al., 1997; van Zuuren et al., 1998; Bilinska-Pietraszek et al., 2001), and, finally, the induction of oral cavity cancers was second to that of liver cancer in patients after bone marrow transplantation (Bhatia et al., 2001). These results indicate the significance of effective immunosurveillance in the prevention of malignancies of the oral cavity. Further corroboration is provided by the high occurrence of both virally- and non-virally-associated lymphomas and Kaposi’s sarcomas in patients with HIV-1 infection (Goedert et al., 1998). In addition, there is substantial evidence indicating that immune responses are inhibited by oral tumors, and this may be largely responsible for their induction and progression. This review focuses on emerging transcriptional mechanisms by which oral tumors may deplete the numbers of immune effector cells and inhibit their function.

Immunosurveillance in the Prevention of Cancer
The theory of immunosurveillance was initially proposed (Burnet, 1970) to indicate that the key thymus-dependent effectors were responsible for eliminating developing cancers (Burnet, 1971a,b). However, the opponents of the theory of immunosurveillance strongly criticized the concept, primarily due to the lack of data showing elevated susceptibility to cancer in nude mice with T-cell defects (Stutman, 1979a,b). More recently, analyses of data obtained from severely immunocompromised STAT1-/- and RAG-/- mice, which have defects in both the innate and adaptive immune effector functions, have revived the concepts of immunosurveillance, and highlighted the significance of both innate and adaptive immune responses in the prevention of cancer (Shankaran et al., 2001; Dunn et al., 2002, 2004; Aggarwal, 2004).

The concept of immunosurveillance has recently been expanded to include immunoediting as an important mechanism for the development of cancer (Dunn et al., 2002, 2004). Cancer immunoediting consists of three phases: elimination, equilibrium, and escape (Dunn et al., 2004). Elimination represents the classic concept of immunosurveillance. However, during equilibrium and escape, the interaction and cross-signaling between the immune effectors and the tumor cells may shape each other by the progressive generation of tumors capable of gradual inactivation and death of the immune effector cells. The final stages of cancer development may result in the induction of less-immunogenic tumors in the presence of fewer immune effectors capable of eliminating the tumor cells. Thus, pressures exerted mutually by tumor cells and immune effectors may eventually shape the environment for the invading tumors. Indeed, our studies with NK-sensitive and -resistant tumors indicated that both cell types are capable of inducing cell death in NK cells (Jewett and Bonavida, 1995, 1996).

Immune Responses in Head and Neck Cancers
Head and neck cancers represent about 6% of all new cancers in the United States (Whiteside et al., 1996). Survival of patients with head and neck cancers has not improved in the last 40 years, despite recent advances in surgical procedures and the availability of new chemotherapeutic agents. There is substantial evidence indicating that immune responses, which should otherwise suppress or eliminate oral cancer cells, are inhibited by properties and functions of oral cancers. NK cells and cytotoxic T-cells, which play crucial effector functions in the host defense against neoplasia, are functionaly inactivated in oral cancers (Trinchieri, 1989; Jewett and Bonavida, 1996; Jewett et al., 1996, 1997, 2003, 2006a; Laad et al., 1996). Regressing tumor grafts of oral origin contain significantly larger numbers of functional NK and T-cells than those associated with the primary tumors (Thomas et al., 1995), while patients with metastasis of head and neck cancers have low NK and T-cell activity (Schantz et al., 1986). Spontaneous apoptosis of circulating peripheral blood T-cells and decreased frequencies of key peripheral blood dendritic cell subsets, attributable to the presence of tumors, are important indicators of total immune cell paralysis in head and neck cancers (Hoffmann et al., 2002).

Immunotherapy with cytokines or adoptively transferred effector cells is less effective in head and neck cancer patients (Cortesina et al., 1988; Rivoltini et al., 1990; Whiteside et al., 1993), than in those with metastatic melanomas or renal cell carcinomas, whereas immunotherapy has been successful in a proportion of the patients (Whiteside et al., 1996). The reason for the failure of known therapeutic modalities in head and neck cancer patients is poorly understood. It has been hypothesized that a widespread, although not complete, absence or paralysis of cytotoxic cells residing inside the inflammatory infiltrate of advanced cancer patients is the main reason for poor prognosis (Hayry and Totterman, 1978; Zoller et al., 1978). Furthermore, freshly isolated tumor-infiltrating lymphocytes are not cytotoxic to autologous tumor cells and show a significantly reduced clonogenicity (Itoh et al., 1986; Miescher et al., 1988; Han et al., 1997; Qin et al., 1997). Indeed, human squamous cell carcinomas of the head and neck have been among the tumors that induce the least-detectable cell-mediated anti-tumor immune responses (Okada et al., 1997). Functional paralysis of cytotoxic cells has also been reported in a variety of other cancers, notably breast (Camp et al., 1996; Gimmi et al., 1996; Marrogi et al., 1997; Hartveit, 1998), renal (Kolenko et al., 1997), and colon (Mulder et al., 1997). More importantly, depletion of cytotoxic effector cells in the tumor milieu has an unfavorable outcome for survival in cancer patients (Bethwaite et al., 1996; Clemente et al., 1996; Marrogi et al., 1997; Wada et al., 1998). Indeed, a significantly shorter survival rate is reported for colorectal carcinoma patients with little or moderate NK infiltration, as compared with those with extensive infiltration (Coca et al., 1997). A five-year survival advantage was also seen with higher CD3-positive tumor-infiltrating T-cells than with a lower T-cell count in uterine cervical carcinoma (Bethwaite et al., 1996). In primary cutaneous melanoma, a five-year survival rate for high tumor-associated lymphocyte infiltrate was 77%, with medium lymphocyte infiltrate 53%, and, for tumors lacking tumor-infiltrating lymphocytes (TILs), 37% (Clemente et al., 1996), suggesting an important function for NK and cytolytic T lymphocytes (CTLs) in cancer cell rejection.

Defects in NK, T, and DCs have been reported in oral cancer patients. Signaling abnormalities, spontaneous apoptosis, and reduced proliferation of circulating NK and T-cells, DCs, and TILs have been reported in patients with oral cancers (Hoffmann et al., 2002; Reichert et al., 2002). The percentage of myeloid-derived LIN^–DR⁺CD11c⁺ DCs is significantly lower in head and neck cancer patients when compared with that in healthy control individuals (Hoffmann et al., 2002). A decrease in the number of DCs in patients was related to the presence of tumor cells, since the numbers of myeloid-derived DCs returned to normal levels when the tumors were excised in patients with head and neck cancers (Hoffmann et al., 2002).

	MECHANISMS OF IMMUNOSUPPRESSION BY TUMOR CELLS

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Many mechanisms have been proposed for the functional inactivation of tumor-associated lymphocytes (Camp et al., 1996; Gimmi et al., 1996; Kolenko et al., 1997; Mulder et al., 1997; Bennett et al., 1998) (Table 1). Soluble products derived from renal cell carcinoma inhibit the proliferative capacity of T-cells infiltrating human tumors, due to a down-regulation of Janus kinase 3 (Jak 3), p56 (Lck), p59 (Fyn), and Zap 70 (Kolenko et al., 1997). Expression of Fas ligand by many human tumor cells, including oral tumors, has been hypothesized to be a major cause of lymphocyte depletion in the tumor microenvironment (Bennett et al., 1998). In mice, tumor-induced immunosuppression has been associated with a decreased expression of the zeta-chain of the T-cell receptor and the loss of mRNA for granzyme B (Mulder et al., 1997). Indeed, as observed in mice, the frequency of TCR-zeta-positive and granzyme-positive lymphocytes is decreased in advanced-stage head and neck carcinomas, and the restoration of expression during in vitro stimulation suggests the presence of tumor-derived suppressive factors (Mulder et al., 1997). Decreased CD16 and its associated zeta chains are also observed in tumor-infiltrating NK cells of patients with cancer (Nakagomi et al., 1993). The relative lack of IFN- and granulocyte-macrophage colony-stimulating factor (GM-CSF), rather than a deficiency of IL-2 by tumor-infiltrating lymphocytes (TILs) in breast cancer, has been hypothesized to be a mechanism for impaired immune function (Camp et al., 1996). Moreover, the breast-cancer-associated antigen DF3/MUC1 has been shown to induce apoptosis of activated human T-cells (Gimmi et al., 1996).

	IMMUNOSUPPRESSIVE FACTORS INDUCED IN THE TUMOR MICROENVIRONMENT

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Interleukin (IL)-6
IL-6 is secreted constitutively by oral squamous cell carcinomas (Thomas et al., 2004), and is found to be elevated in oral cancer patients (Rhodus et al., 2005). IL-6 is known to interfere with IFN- signaling by the induction of Th2 differentiation via activation of NFAT and secretion of IL-4, which subsequently inhibits Th1 polarization via STAT3-induced expression of Suppressor Of Cytokine Signaling (SOCS)-1 in CD4+ T-cells (Diehl and Rincon, 2002) (Tables 1, 2). Gene-targeting experiments have shown that IL-6-deficient mice contain elevated numbers of mature dendritic cells, suggesting that IL-6 negatively regulates DC maturation (Park et al., 2004). In support of a role for IL-6 in mediating immune evasion of tumor cells, Menetrier-Caux et al. showed that conditioned medium from human renal cell carcinoma cell lines blocked the differentiation of CD34+ bone marrow cells into immature DCs, and this inhibitory effect could be blocked with antibodies against either IL-6 or granulocyte colony-stimulating factor (G-CSF) (Menetrier-Caux et al., 1998). Further, in other studies, recombinant IL-6 alone could block the differentiation of CD34+ bone-marrow-derived cells to functional DCs, supporting a model in which tumor-derived IL-6 enhances cancer progression by impairing host anti-tumor immunity (Menetrier-Caux et al., 1998).

View this table: [in this window] [in a new window]   Table 2. STAT3 and NFB-dependent Genes Potentially Involved in Immunosuppression by Tumor Cells

Increased numbers of immature DCs were found in the peripheral blood of cancer patients with elevated levels of circulating VEGF (Gabrilovich et al., 1998). Accordingly, when VEGF concentrations similar to those found in cancer patients were injected into mice, the numbers of immature myeloid cells and immature DCs were increased in their peripheral blood. Therefore, increased secretion of VEGF in the tumor microenvironment may prevent the maturation and differentiation of DCs and contribute to poor anti-tumor immune responses in cancer patients.

	IMMUNOSUPPRESSION MEDIATED BY DIRECT CELL-CELL CONTACT

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Contact-dependent immune suppression can occur by engagement of MHC class I molecules on CD8+CD28-suppressor cells with immunoglobulin-like transcript (ILT2 and ILT4) inhibitory receptors on DCs. Blocking of both MHC Class I and ILTs by specific antibodies can reverse immunosuppression (Chang et al., 2002). Similarly, binding of c-type lectin receptors or Killer Immunoglobulin-like Receptors (KIRs) to MHC Class I ligands inhibits NK cell function (D’Andrea et al., 1995; Wagtmann et al., 1995; Lazetic et al., 1996; Brooks et al., 1997; Carretero et al., 1997). In addition, the expression of co-stimulatory molecules, such as B7H1, on tumor cells and inhibitory DCs and T-cells can inhibit T-cell activation and proliferation (Curiel et al., 2003).

	TARGETING TRANSCRIPTION FACTORS IN TUMORS TO RESTORE THE NUMBERS AND FUNCTIONS OF CYTOTOXIC IMMUNE EFFECTORS

TOP ABSTRACT INTRODUCTION MECHANISMS OF IMMUNOSUPPRESSION... IMMUNOSUPPRESSIVE FACTORS... IMMUNOSUPPRESSION MEDIATED BY... TARGETING TRANSCRIPTION FACTORS... DRUGS THAT TARGET TRANSCRIPTION... CONCLUSIONS REFERENCES

 
Although each of the factors indicated above can be targeted for partial restoration of anti-tumor immunity, analysis of recent data obtained from different laboratories (Jewett et al., 2003; Wang et al., 2004) indicates that targeting transcription factors may provide a better strategy, because these upstream regulators (NFB and STAT3) may be responsible for the increased expression of immunosuppressive factors. Targeting these signaling modules is likely to provide the added benefit of blocking tumor progression at multiple stages of cancer development. Therapies that target transcription factors can cripple the progression of oral cancers by directly blocking tumor cell survival and proliferation, as well as by restoring robust anti-tumor immune responses.

Biology and Function of NFB
The activity of NFB is tightly regulated by cytokines and other external regulators (Baeuerle and Henkel, 1994; Verma et al., 1995). In most cell types, NFB is present as a cytoplasmic heterodimer consisting of 50-kDa (p50) and 65-kDa (p65) subunits. Other subunits that can participate in dimer formation, namely, p52, cRel, and Rel B, as well as the precursor proteins of p50, p52, and p100, respectively, have been identified (Bell et al., 2003). Negative regulators of NFB, collectively referred to as inhibitors of NFB (IB), bind to the heterodimer, block NFB nuclear translocation, and repress the expression of NFB target genes. Several IB isoforms—, β, , (p105), and (p100)—have been identified and characterized previously (Baeuerle and Baltimore, 1996; Whiteside et al., 1997; Whiteside and Israel, 1997; May and Ghosh, 1998). NFB exists in a complex with IB in resting cells (Baeuerle and Henkel, 1994; Thanos and Maniatis, 1995). Multiple stimuli, such as radiation or cytokine and growth factor stimulation, induce the phosphorylation of IB on specific serine residues, such as serines 32 and 36 of IB- and serines 19 and 23 of IB-β by IB kinases (Is). IB phosphorylation disrupts the IB-NFB complex and induces IB ubiquitination, resulting in IB degradation and, eventually, translocation of NFB to the nucleus, where it regulates various genes carrying the NFB response elements. Three subclasses of Is—namely, I- (I-1), I-β (I-2), as well as a non-catalytic regulatory isoform, I- (NEMO)—have been identified and characterized, and are essential for NFB activation (Regnier et al., 1997; Scheidereit, 1998; Fischer et al., 1999; Israel, 2000; Karin and Ben-Neriah, 2000). Both tumor necrosis factor- (TNF-) and interleukin-1 (IL-1) can activate NFB (Osbourn et al., 1989; Beg et al., 1993). TNF- utilizes members of the TNF receptor-associated factor (TRAF) family of adaptive molecules for the activation of NFB (Rothe et al., 1995a,b).

NFB in Cancer
Many aggressive and metastatic tumor cells exhibit constitutively elevated NFB activity (Rayet and Gelinas, 1999). NFB activation is causally related to neoplastic transformation and uncontrolled cell growth in many cell types (Rayet and Gelinas, 1999). Human leukemias and lymphomas, as well as human solid tumors, exhibit constitutively activated NFB in the nucleus (Rayet and Gelinas, 1999). However, although previous studies have attributed a significant role to NFB in oncogenesis and tumor progression, relatively fewer studies have been conducted to explore the significance of elevated NFB function in tumor cells in the modulation of immune effector function against the tumor cells (Jewett et al., 2003, 2006a).

Targeting NFB Improves Anti-tumor Immune Responses against Oral Cancer
We have shown previously that NFB nuclear function in HEp-2 cells, a laryngeal tumor cell line previously used as an oral tumor model (Abdulkarim et al., 2002; Jewett et al., 2003; Murakami et al., 2004, 2005), modulates and shapes the function of interacting immune effectors (Jewett et al., 2003, 2006a). The inhibition of NFB by an IB super-repressor in an HEp-2 oral cell line [Hep2-IB_(S32AS36A)] resulted in significant activation of human NK cell cytotoxic function and increased IFN- secretion. Similarly, the inhibition of NFB by Sulindac increased the functional activation of NK and dendritic cells (DCs) and enhanced anti-tumor cytotoxic activity (Jewett et al., 2003, 2006a). Experiments similar to those performed with HEp-2 cells were also conducted with primary human oral tumor cells (UCLA-1) and immortalized human oral keratinocytes (HOK-18). Inhibition of NFB in both cell types resulted in increased survival and function of interacting NK cells (unpublished observations).

NFB Activation in Tumor Cells Alters the Cytokine/Chemokine Profiles of NK Cells
We next evaluated the function, survival, and cytokine/chemokine profiles of NK cells co-cultured with HEp2 and HEp2- IB_(S32AS36A) tumor cells. We found that blocking NFB in HEp2 tumor cells resulted in increased survival and expansion of NK cells (Jewett et al., 2006a). Furthermore, inverse modulation of IFN- and IL-6 cytokine secretion was clearly seen in cultures of NK cells with HEp2- IB_(S32AS36A) cells indicating that blocking of NFB in HEp2 cells serves to switch the balance from Th2 type responses to more of a Th1 type response (Jewett et al., 2006a). Moreover, HEp2-IB_(S32AS36A) cells produced large amounts of pro-inflammatory chemokines MCP-1 and RANTES, suggesting that targeting NFB in tumor cells may improve recruitment of NK and T cells to the tumor microenvironment (Jewett et al., 2006a).

NFB Function in Tumor Cells May Regulate NK Cell Function via the Modulation of Cell-surface Antigens
We have previously shown that NFB is capable of inversely co-modulating ICAM-1 and MHC-Class I antigen expression on HEp2 cells (Jewett et al., 2003). In Hep2- IB_(S32AS36A) cells, the expression of MHC class I antigens was decreased, whereas the levels of ICAM1 adhesion proteins were elevated.

It is well-established that the cytotoxic activity of NK cells and a subset of T-cells is negatively regulated by the interaction of inhibitory NK cell-surface receptors with their corresponding MHC class I ligands on autologous or allogeneic target cells (Binstadt et al., 1997; Leibson, 1997). Conversely, ICAM-1 expression promotes NK-mediated lysis by enhancing NK-target cell-binding. Interestingly, antibodies to inhibitory NK cell receptors were found to block the function of NK cells by inducing NK cell apoptosis (Jewett et al., 2006b; Ida et al., 1997). Inhibition of NFB tumor cells reduced MHC-class expression and prevented induction of cell death in NK and T-cells (Jewett et al., 2006a). Thus, targeting NFB may decrease inhibitory signals delivered by MHC class I antigens and increase NK-tumor cell adhesion through ICAM-1, resulting in increased NK cell activation and anti-tumor cytotoxic activity. These findings suggest that targeting NFB in oral cancers may increase anti-tumor immunity through the synergistic effects of decreased MHC class I expression and enhanced ICAM-I expression on tumor cells. To expand these observations, we are in the process of delineating whether the inhibition of NFB in HEp2 increases the expression of MHC class-I-related chain A (MICA) on tumor cells, which may also contribute to enhanced NK-mediated tumor cell killing.

NFB Knock-down Oral Tumors Treated with IFN- were Unable to Decrease the Viability or Function of NK Cells
IFN- is known to inhibit NK and T-cell function by the induction of MHC-Class I expression on epithelial cells (Jewett et al., 2003). Therefore, its addition to vector-alone transfected HEp-2 cells significantly decreased both the viability and the function of NK cells (Jewett et al., 2003, 2006a). However, even though treatment with IFN- increased the expression of MHC-Class I moderately on the surfaces of HEp2-IB_(S32AS36A) cells, it caused only a slight decrease in the cytotoxicity, cytokine secretion, and viability of NK cells. Thus, the survival and function of NK cells remained considerably higher in the presence of IFN--treated HEp2-IB_(S32AS36A) cells when compared with either untreated or IFN--treated vector-alone transfected HEp2 cells. Therefore, these results indicated that NFB knock-down oral tumors will likely have a much lower capacity to induce tolerance, either by deleting the NK cells or by inhibiting NK cell function.

The addition of NK-resistant oral tumors to NK cells induced significant cell death of NK cells and down-modulated the expression of CD16 and CD94 surface receptors on NK cells (unpublished observations). Likewise, down-modulation of CD16 and CD94 surface receptor expression, and increased induction of cell death in NK cells were observed when CD16 and CD94 receptors were engaged by specific antibodies on NK cells (Jewett et al., 2006b). Therefore, induction of cell death in NK cells by oral tumors could be mediated by the engagement of CD16 and CD94 receptors by specific tumor ligands. More importantly, NK cells induced to undergo cell death in the presence of receptor antibodies contributed significantly to tumor-derived VEGF secretion (Jewett et al., 2006b). Thus, tumor-induced NK cell death may not only result in decreased immunity against oral tumors, but may also actively contribute to tumor growth by increasing VEGF induction by the oral tumors. This will establish a circular pathway by which tumors will increase their survival, resistance, and vascularization, by inducing death of the immune effectors. Blocking NFB in tumor cells will disrupt this circular pathway and switch the balance toward the survival of the immune effectors and lysis of tumor cells.

Targeting NFB for the Generation of Anti-tumor Vaccines
Tumor vaccination is becoming an attractive strategy for therapy in melanoma patients (Cormier et al., 1999; Gasparollo et al., 2001), and this may be the case for oral cancer patients, if effective strategies can be found to increase tumor immunogenicity. NK cells exposed to HEp2 cells were unable to kill tumor targets in a second round of killing. However, pre-incubation of NK cells with HEp2-IB_(S32AS36A) cells enhanced killing of parental tumor targets in a second round of killing. Therefore, these findings suggested that oral tumor cells with impaired NFB activation may be used to "prime" anti-tumor immune responses ex vivo as part of a strategy to expand and activate lymphocytes that would later target tumor cells in vivo. We are in the process of establishing whether specific lysis of tumor cells by CD8+ T-cells can also be augmented by HEp2-IB_(S32AS36A) cells. Our preliminary experiments indicated that DCs loaded with HEp2-IB_(S32AS36A) cells, but not parental HEp2 cells, activate peripheral blood lymphocytes (PBL) to secrete significantly higher levels of TNF-, IFN-, and IL-12, when compared with those obtained either by the DCs alone or by the PBLs alone (unpublished observations). Therefore, the generation of an effective in vitro tumor vaccine by the targeted inhibition of NFB in tumor cells may be one immediate strategy to augment anti-tumor immunity in cancer patients.

Analysis of Gene-targeted Mice with Impaired NFB Function
Targeted deletion of IKK-β, which inhibits NFB function in the epidermis of mice, has previously been shown to lead to inflammatory skin manifestations similar to those seen in patients with Incontinentia Pigmenti (IP) (Pasparakis et al., 2002). Elevated levels of cytokines and chemokines have also been demonstrated in the epidermis of patients and animals with I and Iβ deletions (Berlin et al., 2002; Pasparakis et al., 2002). Detailed analysis of NFB knock-out keratinocytes and immune cell interaction should therefore reveal the cell types in this system that are responsible for elevated cytokine/chemokine production in vivo (i.e., whether it is the property of the I-negative epidermal cells or the infiltrating lymphocytes).

Role of TNF- in Immunosuppression by Tumor Cells
Mice with a keratinocyte-specific deletion of I-β demonstrated decreased proliferation of epidermal cells and developed TNF--dependent inflammatory skin disease (Pasparakis et al., 2002). In contrast, in other studies in which NFB function was blocked in dermal keratinocytes by a mutant IB-, increased proliferation and hyperplasia (Seitz et al., 1998), and eventual development of cutaneous squamous cell carcinomas of skin, were seen if mice were allowed to survive and reach adulthood (van Hogerlinden et al., 1999, 2004). In contrast to the results obtained in epidermis, blocking of NFB with a mutant IB- super-repressor in HEp2 cells moderately decreased the rate of tumor cell growth, when compared with vector-alone transfected HEp2 cells (unpublished observations). Furthermore, even though HEp2-IB_(S32AS36A) cells were capable of forming tumors in nude mice, the size of the tumors was considerably smaller than that of those obtained by the injection of vector-alone transfected HEp2 cells (unpublished observations).

It is of interest to note that, in these conflicting studies with diverse functional outcomes in keratinocytes, blocking TNF- function resulted in the prevention of both the neoplastic transformation and the inflammatory skin disease (Pasparakis et al., 2002; van Hogerlinden et al., 2004). Thus, it appears that TNF- is the primary factor mediating the pathological processes in both of these studies. In agreement with these findings, we have also observed increased NK cell function in TNF- knock-out mice, indicating that TNF- might also be responsible for decreased function of NK cells (unpublished observations), suggesting that loss of NK cell-mediated immune surveillance might be responsible for neoplastic transformation in mice with keratinocyte-specific inhibition of NFB. Indeed, our previous studies established TNF- as one of the primary factors responsible for the induction of cell death in NK cells (Jewett et al., 1997). Thus, targeting NFB alone in epithelial tumors may not be sufficient to eliminate the tumors entirely. Therefore, along with the inhibition of NFB in tumors, other important inhibitory factors, such as TNF- and IL-6, may need to be targeted before optimal outcomes can be achieved. We are currently addressing these issues in our laboratory.

Role of NFB in Intestinal Tumors
Blocking of NFB function by deleting I-β in intestinal epithelial cells dramatically decreased the rate of tumor formation without affecting the sizes of the tumors in a colitis-associated cancer model (Greten et al., 2004; Greten and Karin, 2004). Moreover, deleting I-β in myeloid cells in the same model system resulted in a decrease in tumor size. These studies also underscore the significance of the cross-talk between different subsets of immune effectors with epithelial cells in the induction and progression of intestinal tumors. Thus, delineating the fine interaction between different immune effectors and established oral tumor models in our laboratory may not only be important in establishing the underlying mechanisms of tumor formation in the oral cavity, but also it may provide a simpler in vitro cell base system for dissecting and identifying the beneficial tumor-inhibitory immune effector functions from the more detrimental tumor-enhancing effector functions. In this regard, oral tumors induce significant amounts of TNF- and IL-6, but not IFN-, release from naïve peripheral blood mononuclear cells, and this, in turn, may be responsible for the induction of cell death in cytotoxic immune cells (Jewett et al., 2003, 2006a).

Other Functions of NFB in Tumorigenesis
The role of the NFB family of transcription factors as tumor promoters has been firmly established previously; however, there are other studies that suggest a tumor suppressor role for NFB function (Seitz et al., 1998; Dajee et al., 2003; Aggarwal, 2004; Perkins, 2004; van Hogerlinden et al., 2004). It appears that the duality of NFB function as either a tumor promoter or tumor suppressor largely depends on the cell type, the stage of maturation, and the nature and extent of mutations sustained by the cells prior to the modulation of NFB function. Thus, at the earlier stages of tumorigenesis, NFB in certain cell types may behave as a tumor promoter, whereas, at the later stages, it may act as a tumor suppressor, when the cells have accumulated mutations at the critical sites. However, in either case, changes in NFB function in tumor cells may profoundly affect the function and survival of the cytotoxic immune effectors. Indeed, a decrease in cellular NFB function may well be one of the important "danger signals" required for the homing and expansion of cytotoxic immune effectors at the site of pathology, to eliminate transformed tumor cells (Fig. 1).

View larger version (25K): [in this window] [in a new window]   Figure 1. Hypothetical representation of the steps involved in recruitment, activation, and expansion of NK cells by HEp2- I B(S32AS36A) cells. NFB knock-down HEp2 tumor cells, by producing large amounts of chemokines MCP-1 and RANTES, recruit NK cells. Due to a decrease in inhibitory signals—provided, for instance, by inhibitory MHC Class I antigens, IL-6 cytokine, and VEGF—NK cells remain viable and increase their functional activation at the site of pathology. Increased survival, in addition to augmented proliferation, results in significant expansion of the NK cells.

Proposed Model of NFB-mediated Immunosuppression by Oral Tumors

Role of STAT3 in Immunosuppression
To target correctly the specific signaling pathways that enable tumors to avoid immune responses, molecular profiling is required to identify constitutively activated signaling modules that are common to most or all cancers that repress anti-tumor immunity. By these criteria, Jak-STAT signaling is an attractive candidate pathway, particularly because all of the cytokines and growth factors that impair host anti-tumor immune responses (VEGF, EGF, IL-10, IL-6, etc.) activate STAT3. Thus, the STAT pathway may be a mechanistic common denominator for all immunosuppressive factors produced by tumor cells.

It has recently been shown that constitutive STAT3 activation in transformed cells acts on the tumor to prevent recruitment of lymphocytes to areas of tumor invasion. In addition, immunosuppressive factors produced by tumor cells induce STAT3 activation in lymphocytes and antigen-presenting cells, blocking their normal function. These recent findings demonstrate that a critical circuit of STAT3 activation in both tumor cells and host components of the immune system cooperates to impair anti-tumor immunity (Wang et al., 2004; Burdelya et al., 2005).

Possible inhibitory effects of STAT3 activation in tumors are:

1. decreased cytokine/chemokine expression by tumor cells, which blocks T-cell recruitment to the tumor (Wang et al., 2004);
   
2. decreased DC maturation, due to the production of cytokines that increase STAT3 activation in DCs (EGF, VEGF, IL-6, IL-10, G-CSF, M-CSF, GM-CSF) (Gabrilovich et al., 1996; Wang et al., 2004);
   
3. increased IL-10-mediated suppression of T-cell and macrophage activation and proliferation via up-regulation of p19 (O’Farrell et al., 2000); and
   
4. increased COX-2 expression, which, in turn, activates IL-6 and STAT3 (Dalwadi et al., 2005).
   

STAT3 is a ubiquitously expressed transcription factor that is activated by multiple cytokines and growth factors, particularly IL-6, IL-10, and EGF (O’Farrell et al., 2000; Cacalano et al., 2001; Levy and Darnell, 2002; Heinrich et al., 2003). In addition, STAT3 is commonly over-expressed and constitutively activated in tumors from a wide variety of tissues and organs, including those of head and neck cancers (Nagpal et al., 2002). Of head and neck squamous cell carcinomas, 58.9% demonstrated very high levels of STAT3 protein accumulation, whereas only 23.2% demonstrated intermediate and 17.8% were low for STAT3 expression. Only baseline levels of STAT3 could be detected in normal samples (Nagpal et al., 2002). While it has been established that STAT3-dependent changes in gene expression contribute to oncogenic transformation, analysis of recent data obtained in our laboratory and others provides evidence that constitutive STAT3 activation in tumor cells plays a key role in suppression of anti-tumor immunity (Wang et al., 2004; unpublished observations).

STAT3 activation in tumor cells negatively regulates macrophage, neutrophil, and T-cell function. Murine peritoneal macrophages treated with supernatants from the B16 murine melanoma cell line produced very low levels of nitric oxide and RANTES (Wang et al., 2004). In contrast, macrophages produced much higher levels of these pro-inflammatory mediators when treated with supernatants from B16 cells expressing Dominant Negative STAT3 (DN-STAT3β) (Wang et al., 2004). In addition, mice injected with DN-STAT3 transfected B16 tumors had dramatically higher levels of macrophage and neutrophil infiltration compared with tumors induced with the parental B16 cell line (Wang et al., 2004). Likewise, supernatants from the tumor cell lines suppressed CD4⁺ T-cell-mediated antigen-specific proliferative responses, as well as CD8⁺ Ag-driven IFN- production, and this effect was abolished if the tumor cells expressed DN-STAT3 (Wang et al., 2004).

Treatment of CD11c⁺ dendritic cells with B16 tumor cell supernatants resulted in reduced expression of IL-12, MHC class II, and CD40 on DCs (Wang et al., 2004). These inhibitory effects were reversed when DN-STAT3 was expressed in B16 tumor cells. Furthermore, constitutive STAT3 activation in tumor cells was shown to inhibit DC function by the increased induction of STAT3 in immature DCs (Wang et al., 2004). Moreover, treatment of immature DCs or bone-marrow-derived mononuclear cells (DC precursors) with tumor cell supernatants resulted in marked reduction in the expression of MHC class II and the CD86 co-stimulatory molecules (Wang et al., 2004). The immunosuppressive effects of tumor-derived factors were abrogated in cells expressing either the DN-STAT3 or in Bone Marrow Progenitor Cells (BMPC) from STAT3 knock-out mice (Wang et al., 2004). In addition, the immunosuppressive effects of tumor cell supernatant on DC differentiation could also be abrogated by the treatment of bone marrow progenitor cells with a phosphopeptide that binds the STAT3 SH2 domain and blocks downstream STAT activation (Wang et al., 2004). IL-6-mediated suppression of dendritic cell maturation was also abrogated in STAT3-deficient bone marrow cells, indicating the significance of STAT3 in IL-6-mediated suppression of DC maturation and function. Analysis of these data suggests that immunosuppression mediated by tumor cells results from a circuit of STAT3 signaling that begins in tumor cells and eventually activates inhibitory STAT3 signaling in dendritic cells and other APCs.

Role of STAT3-mediated Immunosuppression in Glioblastomas
In support of a critical role of STAT3 in immune evasion of tumor cells in humans, we and others have recently showed that glioblastoma multiforme (GBM) tumors display constitutive activation of STAT3 (Rahaman et al., 2002; Jewett and Cacalano, unpublished observations), and poorly induce activating cytokines and tumor-specific cytotoxicity in human peripheral blood mononuclear cells (PBMCs) (unpublished observations). Ectopic expression of dominant-negative STAT3 in the GBM cells increased lysis of the tumor cells by the immune effectors, and induced production of IFN- by the interacting immune effectors (unpublished observations). We are presently delineating the role of activated STAT3 in tumor-mediated repression of lymphocyte activation and antigen-presenting cell function in the context of oral cancers.

Since NFB has been shown to regulate IL-6 secretion in HEp2 cells, and secreted IL-6 in tumors is known to activate STAT3 expression and function, an increase in NFB nuclear function should, in turn, induce STAT3 activation and result in a significant potentiation of immunosuppressive function of tumor cells. Our hypothetical model illustrates the relationship between NFB and STAT3 in the induction of immunosuppression by the tumor cells (Fig. 2). Therefore, targeting STAT3 or signaling pathways upstream of STAT3, such as NFB, may hold great promise in potentiating host anti-tumor immune responses in cancer patients.

View larger version (25K): [in this window] [in a new window]   Figure 2. Cytokines and growth factors produced by tumor cells impair host anti-tumor immunity by activating STAT3 signaling in both tumor cells and professional antigen-presenting cells. Tumor cells expressing constitutively active NFB and STAT3 produce greatly reduced levels of RANTES and IP-10, thereby impairing T-cell infiltration and migration to the sites of tumor growth. In addition, several tumor-derived cytokines and growth factors activate STAT3 in immature dendritic cells, which blocks DC differentiation and expression of co-stimulatory molecules such as CD80 and CD86. High levels of immature DCs (iDC) can actively induce T-cell tolerance to tumor antigens and promote cancer progression.

	DRUGS THAT TARGET TRANSCRIPTION FACTORS IN CANCER

TOP ABSTRACT INTRODUCTION MECHANISMS OF IMMUNOSUPPRESSION... IMMUNOSUPPRESSIVE FACTORS... IMMUNOSUPPRESSION MEDIATED BY... TARGETING TRANSCRIPTION FACTORS... DRUGS THAT TARGET TRANSCRIPTION... CONCLUSIONS REFERENCES

NSAIDs have received considerable attention as chemopreventive drugs and as an adjunct therapy for many cancers. They function partly by decreasing the levels of different prostanoids (Thun et al., 2002). Both COX1 and COX2 have been shown to have important roles in the development of cancer. Deletion of either COX1 or COX2 genes in Apc-deficient mice caused a 70% to 80% reduction in intestinal polyposis (Thun et al., 2002). The induction of both COX1 and COX2 is inhibited by non-selective NSAIDs, such as Sulindac. In contrast, the more selective NSAIDs, designated as coxibs, affect COX2 but not COX1 expression, and they are favored because of their lower systemic toxicity (Thun et al., 2002). However, the analysis of recent clinical data regarding the potential side-effects of coxibs generated concern about long-term use of these classes of drugs in patients (Psaty and Potter, 2006; Zhang et al., 2006). Furthermore, whether coxibs have effects similar to, lower than, or superior to those of the non-selective NSAIDs in cancer prevention and treatment awaits future investigation. It should be emphasized that NSAIDs can function through prostaglandin-dependent and -independent pathways (Thun et al., 2002). Sulindac has been shown to effect myc, NFB, and MAP kinase signaling pathways (Thun et al., 2002). The presence of multiple signaling defects, reported in a variety of cancers, underscores the requirement for a broad therapeutic modality with a capacity for collective targeting of several signaling defects in cancers.

	CONCLUSIONS

TOP ABSTRACT INTRODUCTION MECHANISMS OF IMMUNOSUPPRESSION... IMMUNOSUPPRESSIVE FACTORS... IMMUNOSUPPRESSION MEDIATED BY... TARGETING TRANSCRIPTION FACTORS... DRUGS THAT TARGET TRANSCRIPTION... CONCLUSIONS REFERENCES

 
Recent advances in our understanding of anti-tumor immune responses and cancer biology have revealed a complex dynamic interaction between the immune effectors and the tumor cells. Effectors of the immune system are known to shape tumor cells (immunoediting) and select for cancers with reduced immunogenicity and enhanced capacity to actively induce immunosuppression. Much work has been done to identify strategies by which tumor cells evade the function of the immune system. Altered expression of ICAM-1 and MHC molecules, which block recognition and activation of T- and NK cells, is an example of mechanisms by which tumor cells evade the function of immune system. In addition, tumor cells—by releasing immunosuppressive factors such as Fas, VEGF, IL-6, IL-10, TNF-, GM-CSF, and IL-1β—induce T-and NK cell apoptosis, block lymphocyte homing and activation, and impair macrophage and dendritic cell function. Most importantly, progress has been made in the identification of the upstream mechanisms that control the expression of immunosuppressive factors in tumor cells. Two key control elements, NFB and STAT3, have been identified and shown, coordinately, to regulate the production of multiple tumor-derived immunosuppressive molecules and to play a pivotal role in tumor cell immune evasion. The potential for these two signaling modules to repress immune responses is underscored by the finding that the pathways interact and may even amplify each other. One model for NFB-STAT3-mediated immunosuppression suggests that NFB-induced IL-6 expression activates STAT3 in tumor cells and modulates the production of inhibitory cytokines and chemokines, resulting in impaired T-cell infiltration and activation.

What is most striking is the finding that NFB and STAT3 induce immunosuppression in the tumor microenvironment at many stages of the anti-tumor immune responses. For example, STAT3 appears to function in a feedback loop in which STAT3 activation in tumor cells induces the production of cytokines that trigger inhibitory STAT3 signaling in developing DCs and macrophages.

The studies summarized here shed new light on the mechanisms of immunosuppression by solid tumors, and suggest that targeting NFB and/or STAT3 is likely to be beneficial at multiple levels, such as directly impairing tumor cell survival and proliferation, blocking the production of inhibitory cytokines, improving T-cell chemotaxis, and restoring NK and DC maturation and function. Such targeted therapies hold great promise for immunotherapy of cancer and the improvement of long-term patient survival.

	ACKNOWLEDGMENTS

 
This work was supported by RO1-DE12880 from NIDCR-NIH. The authors acknowledge the expert help of Purvi Vakil in preparation of the manuscript.

Received for publication August 7, 2005. Revision received March 22, 2006. Accepted for publication June 12, 2006.

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Journal of Dental Research, Vol. 85, No. 12, 1061-1073 (2006)
DOI: 10.1177/154405910608501201


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