The tumor cell signaling pathways that trigger the uncontrolled proliferation, resistance to apoptosis, metastasis and escape from immune surveillance are partially understood. Toll-like receptors (TLRs), which recognize a variety of pathogen-associated molecular patterns, are centrally involved in the initiation of the innate and adaptive immune responses. However, recent evidence shows that functional TLRs are also expressed on a wide variety of tumors suggesting that TLRs may play important roles in tumor biology. Activation of tumor cell TLRs not only promotes tumor cell proliferation and resistance to apoptosis, but also enhances tumor cell invasion and metastasis by regulating metalloproteinases and integrins. Moreover, the activation of TLR signaling in tumor cells induces the synthesis of proinflammatory factors and immunosuppressive molecules, which enhance the resistance of tumor cells to cytotoxic lymphocyte attack and lead to immune evasion. Thus, the neoplastic process may usurp TLR signaling pathways to advance cancer progression, which suggests that targeting tumor TLR signaling pathways may open novel therapeutic avenues.
Dynamic interaction between tumors and the immune system is essential for tumor survival, growth and metastasis (Yu et al., 2007). Tumors are infiltrated with large number of immune cells that constitute a major cell population in the tumor microenvironment. Tumor cells depend on their microenvironment to provide signals for growth, antiapoptosis, angiogenesis and metastasis (Hanahan and Weinberg, 2000). However, tumor cells are also under the surveillance due to their recognition by immune cells as foreign. Therefore, tumors have to overcome such immune surveillance to progress. Analysis of the interactions between tumor cells and the host's immune system has led to the realization that tumor cells have devised multiple strategies to evade immune attack. For example, tumors secrete transforming growth factor-β and vascular endothelial growth factor, which inhibit dendritic cell activation and impair tumor-specific T-cell immunity (Vicari et al., 2002). To escape attack from natural killer cells and cytotoxic T lymphocytes (CTL), tumor cells upregulate certain surface molecules (B7-H1 and HLA-G), downregulate others (MHC class I and Fas), and shed some surface molecules in soluble form such as MIC, the ligand for NKG2D (Gratas et al., 1998; Dong et al., 2002; Rouas-Freiss et al., 2003; Wu et al., 2004). However, the signaling pathways controlling expression by tumor cells of factors/molecules that are important for tumor cell immune evasion are not well characterized. Toll-like receptor (TLR) signaling, critical for innate and adaptive immune responses, has been thought to be restricted to immune cells (Iwasaki and Medzhitov, 2004). However, recent studies suggest that tumor cells bear TLRs and that TLR signaling promotes tumor growth and immune evasion (Huang et al., 2005, 2007; Kelly et al., 2006).
TLRs are essential for immune defense against microbes and viruses
Toll-like receptors, expressed on sentinel cells of the immune system, including macrophages and dendritic cells (DCs), are the key sensors of pathogen invasion (Miyake, 2007). Currently, 13 mammalian-TLR analogs have been identified. TLRs 1, 2, 4, 5 and 6 are expressed on the cell surface; TLRs 3, 7, 8 and 9 are found almost exclusively within endosomes. Different TLRs exhibit specificity for pathogen-derived ligands; TLRs 2, 3, 4, 5, 7 and 9 recognize bacterial lipoproteins, double-stranded RNA/poly (I:C), lipopolysaccharides, flagellin, single-stranded RNA and CpG-containing DNA, respectively (Poltorak et al., 1998; Aliprantis et al., 1999; Hemmi et al., 2000; Alexopoulou et al., 2001; Hayashi et al., 2001; Heil et al., 2004). The ligands for TLRs 10, 12 and 13 remain unidentified. TLR10 is expressed in humans but not in mice, TLR8 is not functional in mice and TLRs 11, 12 and 13 are expressed in mice but not in humans.
The signaling pathways utilized by TLRs differ, which result in varied cellular responses. For example, TLR3, the receptor for double-stranded RNA couples to the adaptor protein TRIF. This pathway culminates in activation of TRAF3 and IRF3, resulting in the secretion of IFN-β, which is required for an effective antiviral response. In contrast, other TLRs couple to the adapter myeloid differentiation primary response gene 88 (MyD88) (Takeda and Akira, 2004; O'Neill, 2006). The MyD88-adapter protein recruits IRAKs and TRAF6. The TRAF6 in turn activates TAK1 that phosphorylates and activates the IKK complex culminating in the release and translocation of NF-κB to the nucleus. TAK1 also activates stress-activated protein kinase (SAPK) pathways and activates c-Jun-NH2-kinases (JNK) and p38. The MyD88-coupled TLRs induce the synthesis of cytokines such as TNF-α, IL-6 and IL-1, key mediators of the inflammatory response (Kawai and Akira, 2005; Akira et al., 2006). TLR4, the receptor for lipopolysaccharide, is unique in that it activates both MyD88-dependent and TRIF-dependent pathways. TLR signaling also activates DCs and macrophages to secrete IL-12, a cytokine that directs the adaptive immune response toward a Th1 phenotype. TLRs play a major role as the initiator of the innate immune responses to defend against bacteria, viruses and other pathogens and also required for an effective secondary immune response.
TLR signaling and cancer immunotherapy
Cancer immunotherapy based on the induction and activation of tumor-specific CTLs in principle can eradicate even metastatic tumor cells. CTL cytotoxicity can be mediated by different mechanisms: (1) indirect killing through the release of cytokines IFN-γ and TNF-α; (2) induction of apoptosis by FasL expressed on the CTL interaction with Fas on the target cell and (3) direct killing by secretion of perforin and granzymes into the intercellular space (Andersen et al., 2006). Regrettably, antitumor immune tolerance, which impairs the therapeutic effect of antitumor vaccines, is usually induced by tumor-derived factors or tumor-associated suppressor cells (Khazaie and von Boehmer, 2006; Li et al., 2006; Lizee et al., 2006; Serafini et al., 2006; Munn and Mellor, 2007). Microbial products have been utilized as adjuvants to potentiate antitumor immune responses, because of the pioneering work of William Coley with Coley's toxin. We now understand that such adjuvants work by stimulating TLR signaling and activating both innate and adaptive immune responses to enhance tumor immunotherapy. Several TLR agonists have been demonstrated to produce antitumor effects. Okamoto et al. (2006) used Streptococcal agent OK-432 to activate TLR4 signaling, which resulted in an IFN-γ-mediated antitumor immune response. Whitmore et al. (2001, 2004) reported that double-stranded RNA and CpG DNA can synergistically activate innate immunity leading to enhanced antitumor activity. Current efforts to use TLR agonists to enhance tumor immunity are largely focused on TLR7 and TLR9 (Lee et al., 2003; Craft et al., 2005; Pashenkov et al., 2006; Krieg, 2007). TLR7 and TLR9 agonists, nucleic acid analogues improve antitumor immunity in leukemia or solid tumor types and are currently in clinical trials. In addition to the positive regulation by TLR signaling of the immune response, TLR signaling may also decrease or relieve the suppression of regulatory T cells on DCs or CD8+-T cells (Pasare and Medzhitov, 2003; Yang et al., 2004).
Although there are intriguing data about the effects of TLR agonists on tumors, some concerns remain unresolved at the moment. The immune stimulation of TLR agonists may cause subpopulations of splenic DCs to make indoleamine 2,3-dioxygenase, which degrades tryptophan required by effector T cells, and thus may downregulate antitumor immunity and even promote tumor growth (Mellor et al., 2005; Wingender et al., 2006). Regulatory T cells can impair antitumor immune responses (Wang and Wang, 2007). Several groups have recently reported that TLR agonists stimulate the proliferation and suppressor function of regulatory T cells, thus attenuating the antitumor effects discussed earlier (Liu et al., 2006; Sutmuller et al., 2006; Kabelitz, 2007). So far, there have been no definitive reports of induction of systemic autoimmune disease from the administration of TLR agonists. However, studies with TLR agonists as vaccine adjuvants have showed that they provide a remarkable acceleration and amplification of both T- and B-cell responses. Thus, there exists a possibility for the activated T or B cells to attack self-components (Deane and Bolland, 2006; Ehlers and Ravetch, 2007). It remains unclear to what extent TLR-activation will be able to overcome the multiple strategies developed by tumors to evade vaccine-induced antitumor immunity.
Expression of TLRs by tumor cells
The importance of TLR for tumor immunity is evident in an increasing body of evidence that TLR-variants are associated with cancer risk. Zheng et al. (2004) first reported and Chen et al. (2005) and Cheng et al. (2007) confirmed that sequence variants of TLR4 are associated with prostate cancer risk. Subsequently, variants of TLR1, TLR6 and TLR10 were also confirmed to increase prostate cancer risk (Sun et al., 2005). Sequence variants of TLR4 and TLR10 are associated with nasopharyngeal carcinoma risk (Song et al., 2006; Zhou et al., 2006). The risk of gastric carcinoma is increased by a functional polymorphism of TLR4 (Ohara et al., 2006; Hold et al., 2007). The etiology of some lymphoma subtypes is connected to single-nucleotide polymorphisms in TLR1, TLR2, TLR4, TLR5 and TLR9 (Nieters et al., 2006).
Toll-like receptors are expressed on cells of the immune system but we have also found that TLRs are also expressed on tumor cells, where they may influence tumor growth and host immune responses (Huang et al., 2005). We screened murine tumor cell lines of different tissue-origin including MC26 (colon), 4T1 (breast), RM1 (prostate), B16 (melanoma) and LLC1 (lung) for the expression of TLRs (including TLR1-6 and -9) by reverse transcriptase–PCR (RT–PCR). All the tumor cell lines expressed multiple TLRs (Huang et al., 2005). We also screened five human tumor cell lines including HCT15 and SW620 (colon), MCF7 (breast), UACC-62 (melanoma) and MDA-MB435 (breast). The human tumor cell lines also expressed multiple TLRs. TLR9 was most strongly expressed on human tumor lines rather than TLR4, as in murine tumors (unpublished data). Similar results were reported by others. Human lung cancer cells express functionally active TLR9 (Droemann et al., 2005); human gastric carcinoma cells express TLR4, TLR5 and TLR9 (Schmausser et al., 2005); human laryngeal carcinoma cells express TLR2, TLR3 and TLR4 (Szczepanski et al., 2007); human cervical tumor cells express TLR9 (Lee et al., 2007); human NB-1 neuroblastoma cells express an intracellular form of TLR4 (Hassan et al., 2006); human prostate-cancer cells express TLR9 (Ilvesaro et al., 2007) and human melanoma cell lines express TLR4 (Molteni et al., 2006). In addition, many reports indicate that TLRs are expressed on leukemia cells (Bohnhorst et al., 2006; Jego et al., 2006), which is expected since leukemic cells are the immune cells derived from bone marrow. The general expression of TLRs by tumor cells suggests that TLR-signaling may play an important role in tumor development.
Tumor cell TLR-signaling and tumor progression
Activation of TLR expressed on tumor cells may have profound consequences for tumor growth. Tumor immune evasion may be facilitated by inhibitory cytokines, inflammatory factors, proteinases, and other small molecules such as nitric oxide. The sources of such tumor-promoting factors are still poorly understood. We stimulated tumor cells with lipopolysaccharides, the prototypical ligand for TLR4, and found that tumors produce proinflammatory factors including nitric oxide, IL-6 and IL-12 mimicking some characteristics of inflammatory cells. These factors result in resistance of tumor cells to CTL and natural killer cell attack and evasion from immune surveillance (Huang et al., 2005). These effects can be attributed to TLR4 expression since blockade of the TLR4 pathway by either TLR4 siRNA or a cell-permeable TLR4 inhibitory peptide delays tumor growth and thus prolongs the survival of tumor-bearing mice. In another system, we show that Listeria monocytogenes infection of a local tumor can promote tumor growth via the TLR2-signaling pathway, which leads to the production of immunosuppressive molecules such as nitric oxide and IL-6 by tumor cells (Huang et al., 2007). Thus, under some conditions, TLRs expressed by tumor cells do play a role in regulating tumor growth.
Recent evidence suggests that TLRs also contribute to tumor-cell resistance to apoptosis and increased invasiveness. Kelly et al. (2006) find that activation of TLR4 signaling promotes the growth and chemoresistance of epithelial ovarian cancer cells. The expression of X-linked inhibitor of apoptosis, a major inhibitor of caspase-3 and -9 and the expression of Akt have been associated with tumor growth and chemoresistance in ovarian cancer cells. (Yuan et al., 2003; Dan et al., 2004a, 2004b) report that activation of TLR4 in ovarian cancer cells results in a significant increase of X-linked inhibitor of apoptosis and phosphorylated Akt. The inhibition of tumor-cell apoptosis by TLR-signaling is also observed in lymphoma cells and lung cancer cells (Jego et al., 2006; He et al., 2007). The highly invasive MDA-MB-231 breast cancer cell line expresses TLR9, which when activated promotes MDA-MB-231 cell invasion by increasing the activity of matrix metalloproteinase 13 (MMP13), but not MMP8 (Merrell et al., 2006). Moreover, two earlier studies demonstrated that lipopolysaccharides may also promote tumor invasion through the lipopolysaccharides-activated NF-κB pathway resulting in upregulation of iNOS and MMP2 and the β1 integrin subunit (Harmey et al., 2002; Wang et al., 2003). Thus, activation of TLR4 expressed by tumor cells results in adherence to extracellular matrix and endothelial cells promoting invasion and metastasis. In addition, a new in vitro study indicates that TLR9 agonists can stimulate prostate cancer invasion by increasing MMP13 activity (Ilvesaro et al., 2007).
What are the endogenous ligands for tumor cell TLRs?
We and others have shown by using microbial TLR ligands that tumors express a variety of functionally active TLRs but it is not clear what the ligands in the tumor microenvironment are (Huang et al., 2005). We have demonstrated that L. monocytogenes directly affects tumor cells and promotes tumor cell growth through the TLR2-signaling pathway in vivo (Huang et al., 2007) but the endogenous ligands (that is, TLR ligands apart from those of microbial origin) for tumor cell TLRs have not been identified (Berg, 2002; Tsan and Gao, 2004; Rifkin et al., 2005). Identification of endogenous ligands is of obvious interest for tumor biology, but will also be pertinent to dissect the role of TLRs in autoimmune diseases such as systemic lupus erythematosus and chronic sterile inflammatory disorders such as atherosclerosis and arthritis (Xu, 2002; Liu-Bryan et al., 2005; Marshak-Rothstein, 2006; Sioud, 2006).
Heat-shock proteins (HSP) such as HSP60, HSP70 and HSP90 from a variety of sources induce the production of proinflammatory cytokines such as TNF-α, IL-1, IL-6 and IL-12; the release of nitric oxide and C–C chemokines by monocytes, macrophages and DCs (Asea et al., 2000; Kol et al., 2000; Singh-Jasuja et al., 2000). HSP also induce the maturation of DCs as demonstrated by the upregulation of MHC class I and II molecules and co-stimulatory molecules such as CD80 and CD86. Using TLR4 mutant mice and TLR2 KO mice, these functions of HSPs have been shown to proceed through TLR4- or TLR2-dependent pathways. Therefore, HSP60, HSP70 and HSP90 are putative endogenous ligands for TLR4 and TLR2 (Tsan and Gao, 2004; Rifkin et al., 2005). In addition, a recent study indicated that a small HSP (HSP22) may also act as an endogenous TLR4 ligand in the pathogenesis of rheumatoid arthritis (Roelofs et al., 2006). Other molecules besides HSP have been identified as potential TLR ligands including fibrinogen (Smiley et al., 2001), surfactant protein-A (Guillot et al., 2002), domain A of fibronectin (Okamura et al., 2001), heparan sulfate (Johnson et al., 2002), hyaluronan oligosaccharide (soluble hyaluronan) (Termeer et al., 2002), β-defensin 2 (Biragyn et al., 2002) and high-mobility group box 1 protein (Park et al., 2004). These endogenous ligands were characterized with murine cells and are ligands for TLR2 and/or TLR4. These observations are significant since: (1) murine-tumor cells highly express TLR4 (Figure 1); (2) fibrinogen, fibronectin, heparan sulfate and hyaluronan are critical components of the tumor extracellular matrix and all-cause tumor progression (Rybarczyk and Simpson-Haidaris, 2000; Sanderson et al., 2004; Gotte and Yip, 2006; Liu et al., 2007); (3) surfactant protein-A is expressed in lung cancer (Camilo et al., 2006; Iino et al., 2007); (4) β-defensin 2 possesses a strong bactericidal effect on Gram-negative bacteria (Ganz and Weiss, 1997) and is expressed by oral cancer cells (Abiko et al., 1999); (5) although HSPs and high-mobility group box 1 protein are intracellular proteins, they can be passively released from dead cells (Ciocca and Calderwood, 2005; Ellerman et al., 2007) and therefore could be present in the tumor microenvironment.
Apoptosis or programmed cell death, necessary for tissue remodeling and removal of cells that fail to repair a damage, is tightly regulated by many of the same pathways involved in inflammation. In tumors both apoptosis and necrosis occur releasing proteins such as high-mobility group box 1 protein and HSPs that are ligands for TLR2 and TLR4. However, in addition RNA– and DNA– nucleoprotein complexes could also be released, which could also constitute ligands for TLR activation. Chromatin and DNA immune complexes have been proposed as endogenous ligands for TLR9 (Boule et al., 2004; Barrat et al., 2005), and mRNA may be an endogenous ligand for TLR3 (Kariko et al., 2004). We propose that DNA– and RNA–protein complexes released from dying cells act as tumor-facilitating factors by paracrine activation of tumor cell TLR3, TLR7, TLR8 and TLR9. Identification of the endogenous ligands for tumor TLRs would further make us to understand the mechanisms for tumor cell growth and escape from the host defense system. However, excluding microbial contamination such as lipopolysaccharides is a major concern in attempting to identify endogenous TLR ligands (Tsan and Gao, 2004, 2007).
The activation of TLRs is required for host defense against invading microbes and TLR ligands may be utilized as effective immuno-adjuvants in tumor immunotherapy or combined tumor therapy. However, TLR activation may be a two-edged sword, with both antitumor and pro-tumor consequences. The general expression by tumor cells of functionally active TLRs and the broad distribution of putative endogenous ligands suggest tumor cell TLR signaling may be continually activated and contribute to tumor progression. Understanding TLR function in tumor biology may lead to discovery of new therapeutic targets in cancer therapy.
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Dr Huabao Xiong was supported by NIH P01 DK72201, a Crohn's and Colitis Foundation of America, a grant from the Eli and Edythe L Broad Foundation. Dr Zuo-Hua Feng was supported by National Development Program (973) For Key Basic Research (2002CB513100) of China. Dr Jay Unkeless was supported by a Crohn's and Colitis Foundation of America Grant.
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Huang, B., Zhao, J., Unkeless, J. et al. TLR signaling by tumor and immune cells: a double-edged sword. Oncogene 27, 218–224 (2008). https://doi.org/10.1038/sj.onc.1210904
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