Advertisement
CCR Focus

Transforming Growth Factor-β and the Immune Response: Implications for Anticancer Therapy

Stephen H. Wrzesinski, Yisong Y. Wan and Richard A. Flavell
DOI: 10.1158/1078-0432.CCR-07-1157 Published September 2007

Abstract

Immune homeostasis is a delicate balance between the immune defense against foreign pathogens and suppression of the immune system to maintain self-tolerance and prevent autoimmune disease. Maintenance of this balance involves several crucial networks of cytokines and various cell types. Among these regulators, transforming growth factor-β (TGF-β) is a potent cytokine with diverse effects on hematopoietic cells. Its pivotal function within the immune system is to maintain tolerance via the regulation of lymphocyte proliferation, differentiation, and survival. In addition, TGF-β controls the initiation and resolution of inflammatory responses through the regulation of chemotaxis and activation of leukocytes in the periphery, including lymphocytes, natural killer cells, dendritic cells, macrophages, mast cells, and granulocytes. Through its pleiotropic effects on these immune cells, TGF-β prevents the development of autoimmune diseases without compromising immune responses to pathogens. However, overactivation of this pathway can lead to several immunopathologies under physiologic conditions including cancer progression, making it an attractive target for antitumor therapies. This review discusses the biological functions of TGF-β and its effects on the immune system and addresses how immunosuppression by this cytokine can promote tumorigenesis, providing the rationale for evaluating the immune-enhancing and antitumor effects of inhibiting TGF-β in cancer patients.

  • Immune Response
  • TGF-β

The pleiotropic cytokine, transforming growth factor-β (TGF-β), plays a critical role in suppressing the immune response in the periphery to prevent an autoimmune response. TGF-βs are regulatory molecules with numerous effects on cell proliferation, differentiation, migration, and survival that affect multiple biological processes, including development, carcinogenesis, fibrosis, wound healing, and immune responses (1). This system has evolved over the last billion years to regulate immune systems in multicellular organisms (2). The effects of TGF-β on the immune system were first published in 1986 (3). Transgenic mice lacking TGF-β were established in the early 1990s and demonstrated the central role of this cytokine in inhibiting inflammation and autoimmune disease (4, 5). The subsequent identification of TGF-β receptors (TGF-βR) and Smad factors as mediators of receptor signaling pathways revealed the molecular mechanisms behind TGF-β regulation of the immune response (6, 7). At the turn of the 21st century, murine models containing cell type–specific activation of TGF-β signaling have enhanced our understanding of the regulatory network of the TGF-β pathway in vivo (8–12) and how attenuating its function may improve antitumor responses (13). In this review, we discuss the regulatory functions of TGF-β in the immune system as well as how the immunosuppressive effects of this cytokine promotes cancer progression, providing the rationale for developing TGF-β inhibitors as antitumor agents.

TGF-β Expression and Signaling

The TGF-β superfamily consists of a large group of extracellular growth factors controlling multiple aspects of development. TGF-β superfamily members bind and activate transmembrane serine/threonine kinase receptors resulting in intracellular signaling (14). This family contains not only the TGF-βs but also the bone morphogenetic proteins, activins, and growth differentiation factors (14). Three TGF-β isoforms, TGF-β1, TGF-β2, and TGF-β3, have been identified in mammals that have similar biological function but are expressed in different tissues (15). Among these three isoforms, TGF-β1 is predominantly expressed in the immune system. Unlike most cytokines, TGF-β is synthesized as an inactive large precursor molecule containing a self-inhibiting propeptide in addition to the active form of TGF-β. Proteolytic processing results in a heterodimer containing an active TGF-β in association with either a latency-associated protein or latent TGF-β–binding protein, which keeps TGF-β inactive (16). Under physiologic conditions, active TGF-β, either as a cell surface–bound or intracellular soluble form, is liberated from these proteins following additional stimuli from acidic pH, integrins, thrombospondin-1, and proteases, enabling it to exert its function by binding to its receptor (17–21).

Signal transduction follows binding of TGF-β to a heterodimeric receptor complex consisting of type I and II transmembrane serine/threonine kinase subunits. Five type I (activin-like receptor kinase family) and seven type II receptors have been identified to form these TGF-βRs (Fig. 1 ; ref. 14). Intracellular signal transduction is mediated by phosphorylation of several transcription factors known as Smads as well as Smad-independent pathways involving kinase cascades, including Rho-Rac-cdc-42, Ras-extracellular signal-regulated kinase, Tak-MKK3/6-c-Jun NH2-terminal kinase, TAK-MKK4-p38, and phosphatidylinositol 3-kinase, and transcriptional regulators, such as TGF-βR interacting protein, protein phosphatase 2A, elongation initiation factors, and the immunophilin, FK506 binding protein 12 (Fig. 1; refs. 22–25). Following TGF-β binding, the Smad-dependent pathway is activated when activin-like receptor kinase 5 phosphorylates Smad2 and Smad3, which translocate into the nucleus in a complex with Smad4 (Fig. 1). The resulting Smad complex binds to a target promoter and regulates gene expression through the recruitment of histone acetyl transferase or histone deacetylase (Figs. 1 and 2 ; refs. 26, 27). Negative regulators of this pathway include Smad7, which competes with Smad2 and Smad3 for activin-like receptor kinase 5 binding and degrades activin-like receptor kinase 5 through the recruitment of Smurf-containing E3 ubiquitin-ligase complexes. The Smad-independent pathways activated following TGF-β binding to its receptor are poorly understood and their relevance to immune cell regulation is unknown.

Fig. 1.
Fig. 1.

Summary of Smad-dependent and Smad-independent signaling following TGF-β binding to its receptor. Following TGF-β binding to an example of a heterodimeric receptor for this cytokine [activin-like receptor kinase 5 (ALK5) and TGF-βRII], several molecular signaling cascades occur. The Smad-dependent and Smad-independent pathways as well as negative regulatory feedback pathways through Smurf and Smad7 are shown. TF, transcription factor; HAT, histone acetyl transferase; HDAC, histone deacetylase; FKBP12, FK506 binding protein 12; TRIP-1, TGF-βR interacting protein; PP2A, protein phosphatase 2A; eIFs, elongation initiation factors; JNK, c-Jun NH2-terminal kinase; Erk, extracellular signal-regulated kinase; PI3K, phosphatidylinositol 3-kinase.

Fig. 2.
Fig. 2.

Epithelial cell and effector immune cell genes affected following TGF-β binding and signaling in the tumor microenvironment. Examples of epithelial cell genes up-regulated and down-regulated as well as CTL genes that are down-regulated following TGF-β–mediated intracellular signaling are listed.

TGF-β and the Key Effector Cells in the Antitumor Response: T cells and Natural Killer Cells

TGF-β and T cells. CD8+ cytotoxic T cells (CTL) and natural killer (NK) cells play a critical role in the prevention, killing, and clearance of tumors and have been targeted in the development of anticancer immunotherapies (28, 29). As a pleiotropic cytokine, TGF-β exerts its effects on multiple immune cell types (1) and its role in controlling T-cell functions has been extensively studied. TGF-β inhibition of T-cell proliferation in vitro was first documented using activated human T cells (3). One mechanism behind TGF-β–mediated suppression of T-cell proliferation is through TGF-β blockade of the production of interleukin (IL)-2 (Fig. 2), a lymphokine known to activate T cells, NK cells, and other types of cells of the immune system (30, 31). This effect can be partially reversed by the addition of exogenous IL-2 (3). Further work has shown that TGF-β suppression of IL-2 production may be through directly inhibiting IL-2 promoter activity through a cis-acting enhancer DNA element (32). R-Smad3 has also been shown to be critical in mediating TGF-β inhibition of IL-2 production (33).

In addition, TGF-β inhibits T-cell proliferation through pathways not involving IL-2 suppression (3). For example, TGF-β also attenuates the expression of cell cycle regulators in T cells. Upon TGF-β treatment, cyclin-dependent kinase inhibitors, including p15, p21, and p27, are up-regulated, whereas cell cycle–promoting factors, including c-myc, cyclin D2, cyclin-dependent kinase 2, and cyclin E, are decreased (34–39). The functional significance behind these effects of TGF-β as well as how TGF-β modulates these genes in T cells awaits further evaluation.

In addition to suppressing T-cell proliferation, TGF-β also controls T-cell effector functions. The expression of effector molecules by CTLs, such as IFN-γ and perforin, is inhibited by TGF-β (Fig. 2; refs. 40–43). Recent studies have shown that TGF-β is important for the inhibition of the exocytosis of granules and cytolytic function of CD8+ T cells (44). For example, Mempel et al. (44) used multiphoton intravital microscopy in the lymph nodes of anesthetized mice to evaluate how CTLs interact with antigen-presenting target cells in the presence or absence of activated regulatory T cells (Tregs), a suppressive T-cell population identified by the constitutive expression of a forkhead family transcription factor, FoxP3 (44). CTLs killed their targets at a 6.6-fold faster rate in the absence of Tregs, which can inhibit cytotoxic granule exocytosis by these effector cells (44). This effect was dependent on TGF-β as CTLs refractory to signaling by this cytokine displayed normal killing in the presence of Tregs (44).

The critical physiologic role for TGF-β in regulating suppression of conventional CD4+ and CD8+ T cells has been illustrated by studies of genetically modified mice. For example, mice lacking TGF-β1 expression (TGF-β1−/− mice) develop a multifocal inflammatory disease associated with increased inflammatory cytokine production (4, 5, 45). However, because TGF-β1 is pleiotropic and acts on multiple immune cell types, it is unclear from these studies whether T cells were the direct targets of this cytokine. To answer this question, we generated mice expressing a dominant-negative form of TGF-βRII from the CD4 promoter (CD4-dnTβRII) in T cells, which resulted in the expression of the dominant-negative receptor (dnTGF-βRII) exclusively in both CD4+ and CD8+ lymphocytes (9). These mice developed an autoimmune inflammatory phenotype associated with uncontrolled CD4+ T-cell differentiation into effector cells (9). These mice were also resistant to tumor engraftment when challenged with the murine melanoma cell line B16-F10 and murine thymoma cell line EL-4, suggesting that blocking TGF-β signaling in T cells may enhance T-cell–mediated antitumor activity (13). Adoptive transfer experiments revealed that the observed antitumor effects following tumor challenge were dependent on blockade of TGF-β signaling in CD8+ cells and T-cell “help” from either wild-type CD4+ or TGF-β dominant-negative receptor transgenic CD4+ cells (13). In separate experiments conducted by Zhang et al. (46), adoptive transfer of CTLs transfected with the dnTGF-βRII gene produced enhanced antitumor activity, thus confirming the immunosuppressive effects of TGF-β on effector cells and suggesting an approach for enhancing immune antitumor responses in cancer patients.

In addition to its inhibitory effects on the proliferation and the function of conventional T cells, TGF-β further contributes to immunosuppression by promoting the generation of Tregs. Tregs are frequently found at higher frequencies in the peripheral blood, lymph nodes, and tumor sites of cancer patients (47). Although TGF-β can promote the generation of Tregs in vitro, it has been controversial whether TGF-β is involved in the generation or maintenance of Tregs under physiologic conditions. One recent study showed that Tregs lacking the TGF-βRII developed normally in the thymus but were poorly maintained in the periphery (48). That same study also showed that TGF-βRII–deficient Tregs were found to proliferate faster than the wild-type counterparts in the periphery, suggesting that TGF-β signaling is required to promote peripheral Treg survival independent of its proliferation potential (48). These results contrasted with those in other animal models where Treg maintenance or development was unaffected in environments lacking TGF-β1 expression (49). The discrepancies between these studies may be related to different experimental systems and mouse genetic backgrounds used in the experiments. The development of EGFP-FoxP3 and FoxP3-mRFP knock-in mice and FoxP3 intracellular staining will provide improved tools to identify Tregs based on FoxP3 expression (48, 50, 51). These reagents will enable future studies evaluating the effects of TGF-β on Treg biology and how this cytokine and Tregs inhibit antitumor responses in mouse models and cancer patients.

TGF-β and NK cells. NK cells are lymphoid cells that participate in innate immunity and in early defense by recognizing and killing infected or tumorigenic cells and rapidly producing chemokines and cytokines. IFN-γ production by NK cells is considered essential for stimulation of the Th1 response, and TGF-β attenuates this activity as well as the cytolytic activity of these cells (52, 53). Although the mechanisms of TGF-β–mediated inhibition of NK production of IFN-γ are unknown, TGF-β blocks the expression of receptors vital for the cytotoxic function of NK cells. Targeted killing by NK cells depends on the engagement of the NK receptors and coreceptors NKp46, NKp30, NKp44, and NKG2D (54, 55). Exogenous TGF-β inhibits the expression of NKp30 and NKG2D receptors resulting in decreased killing function (56). Our preliminary studies using transgenic mice containing NK cells resistant to TGF-β signaling (10) have revealed enhanced tumor rejection in these mice compared with wild-type littermates.4 Furthermore, down-modulation of NKG2D has also been associated with elevated TGF-β levels in cancer patients (57). This observation shows an immunosuppressive effect of TGF-β on NK cells under physiologic conditions in cancer patients and suggests a mechanism by which these cells are less effective at killing tumor cells. Further studies are planned to evaluate the antitumor effects of specifically blocking TGF-β signaling in NK cells and to determine the contribution of these cells in antitumor responses enhanced by approaches blocking TGF-β more broadly.

TGF-β and Dendritic Cells Involved in the Antitumor Response

Dendritic cells are professional antigen-presenting cells essential for immunity and tolerance (58). They are extremely potent antigen-presenting cells that can initiate antigen-specific immune responses through presentation to T cells as well as activate B cells and NK cells. Because they can activate both the adaptive and innate arms of the immune system, these cells have been targeted for developing cancer vaccines. Cancer vaccines based on administration of antigen-loaded dendritic cells have been used in several clinical trials involving advanced melanoma, renal cell carcinoma, breast cancer, non-Hodgkin's lymphoma, multiple myeloma, prostate cancer, lung cancer, and colorectal cancer patients (reviewed in refs. 29 and 58). However, to date, the majority of cancer patients have not derived clinical benefit (reviewed in refs. 29 and 58).

Improvements in dendritic cell function may be possible through inhibition of TGF-β. TGF-β regulates the antigen presentation function of differentiated dendritic cells. On stimulation with bacterial components, inflammatory cytokines or costimulatory receptors, dendritic cells up-regulate MHC class II and costimulatory molecules and cytokines, including IL-12, which induce T-cell activation and differentiation. Exogenous TGF-β administration to lipopolysaccharide-stimulated dendritic cells inhibits the expression of MHC class II and costimulatory molecules (59). In addition, exogenous administration of this cytokine prevents the production of IL-12 induced by the inflammatory cytokines IL-1 and tumor necrosis factor-α (59). These effects may ultimately result in the inhibition of T-cell activation and differentiation required for an effective antitumor response, thus providing the rationale for evaluation of blocking TGF-β signaling in dendritic cells as well as T cells and NK cells.

TGF-β, the Immune System, and Cancer

High levels of TGF-β are produced by many types of tumors, including melanomas and cancers of the breast, colon, esophagus, stomach, liver, lung, pancreas, and prostate, as well as hematologic malignancies (60, 61). Also, both the TGF-βRs type I and II as well as Smad proteins are mutated in several cancers (reviewed in ref. 62). In addition, tumors can promote TGF-β production by the surrounding cells in the tumor microenvironment (63). In early stages of tumorigenesis, TGF-β seems to act as a tumor suppressor. Gastrointestinal tumors with microsatellite instabilities and mutations in the TGF-βRII and pancreatic cancers containing Smad4 mutations do not respond appropriately to ligand-receptor interactions and thus become resistant to the signaling and antitumor activity by this cytokine (64, 65). During later stages of tumorigenesis, TGF-β can foster tumor growth, progression, and metastasis by enhancing the epithelial to mesenchymal transition and promoting tumor angiogenesis (66, 67). Interestingly, higher levels of TGF-β expression are observed in metastatic breast and colon metastases compared with the primary tumors (68, 69), reinforcing its role in promoting tumor progression in later stages of the disease. Elevated TGF-β levels correspond with poor clinical outcome of cancer patients. High serum TGF-β levels in gastric carcinoma patients have been correlated with earlier recurrence rates for this cohort (70). Retrospective analyses of archival tumors obtained from breast, colon, and lung cancer patients have suggested a relationship between high levels of TGF-β with increased disease progression, metastasis, and death in breast and colon cancer patients and a worse 5-year survival in lung cancer patients (71–73).

In addition to its direct effects on tumor cells and angiogenesis, TGF-β enables tumors to evade immune surveillance (74) and killing through the mechanisms reviewed above and summarized in Fig. 3 . TGF-β promotes Treg generation on TCR stimulation and it is conceivable that tumors promote immune privilege by generating Tregs through TGF-β production. This may be clinically relevant as high levels of Tregs portend a poor prognosis in ovarian cancer patients (75) and these cells infiltrate tumors in patients with various cancers as previously discussed above.

Fig. 3.
Fig. 3.

TGF-β secretion in the tumor microenvironment and its effects on the cellular level. Summary of the immunosuppressive effects of TGF-β on immune cells involved in the antitumor response following its secretion by stromal cells and various tumor cells. CTL, cytotoxic T lymphocytes; Treg, regulatory T cells; NK, natural killer cells; DC, dendritic cells.

The epidemiologic and biological studies implicating TGF-β in tumor promotion and progression provide a strong rationale for developing TGF-β inhibitors as therapeutic agents for advanced cancer. Various inhibitors of TGF-β signaling are being evaluated in preclinical models and early clinical trials including soluble protein receptors, TGF-β antibodies, small-molecule kinase inhibitors, oligonucleotides, peptide aptamers, and tumor vaccines, which are summarized in Table 1 . Currently, the majority of the TGF-β signaling inhibitors are in preclinical studies. However, a blocking oligonucleotide (AP12009), an antibody to all three isoforms of human TGF-β (GC-1008), a small-molecule inhibitor of the TGF-βRI kinase (LY573636), and a vaccine using allogeneic tumor cells have entered clinical cancer trials (76–78).5,6

View this table:
Table 1.

Summary of TGF-β signaling inhibitors

The most advanced studies to date involve approaches inhibiting TGF-β locally, including the synthetic antisense oligodeoxynucleotide, AP12009, and allogeneic tumor vaccines (76–78). The antisense AP12009 can bind to TGF-β2 mRNA in tumor cells, ultimately leading to decreased expression of TGF-β2. In preclinical studies, AP12009 reduced proliferation in glioma, pancreatic cancer, and malignant melanoma cell lines (76). Animal studies further showed that intrathecal bolus injections and intracerebral infusions of AP12009 were well tolerated (76). Subsequent phase I/II open-label dose escalation studies showed that this compound was safe and well tolerated when administered as intratumoral injections to patients with high-grade gliomas (76). Following treatment with AP12009, patient-derived peripheral blood mononuclear cells showed enhanced immune cell–mediated cytotoxicity against tumor cells in vitro after stimulation with IL-2 and coincubation with autologous glioma cells (76). These results suggest that this oligodeoxynucleotide may enhance antitumor responses in glioma patients and warrant further evaluation in larger clinical trials. To this end, an international phase II trial in adult patients with recurrent high-grade glioma has recently completed enrollment (76). Given that AP12009 also inhibits pancreatic cancer and malignant melanoma cell lines, phase I/II studies evaluating this compound in pancreatic carcinoma and malignant melanoma patients are also under way (76).

Clinical studies have also been initiated with an allogeneic whole-cell tumor vaccine that has been stably transfected with a TGF-β2 antisense plasmid vector. Expression of this vector leads to reduced TGF-β2 expression by the vaccine cells (77), which could be an advantage considering that the endogenous TGF-β generated by the whole-cell vaccine might inhibit its efficacy. Gliosarcoma (9L) cells were stereotactically implanted in the forebrains of Fisher 344 rats and the animals were immunized with irradiated 9L cells stably transfected with a TGF-β2 antisense vector (pCEP-4 TGF-β) 5 days later (79). All (11 of 11) of the vaccinated rats survived 12 weeks compared with 2 of 15 and 3 of 10 rats vaccinated with gliosarcoma cells transfected with an empty vector or the IL-2 gene, respectively (79). Furthermore, a cohort of surviving rats rechallenged with 9L cells 12 weeks following vaccination survived for 6 months compared with a 5-week survival for unvaccinated control rats (79), suggesting that the vaccine induced a sustained antitumor response with immunologic memory. At necropsy, histopathology of the tumor implantation sites revealed no microscopic evidence of the originally implanted tumor cells (79). These results are surprising given that TGF-β was only inhibited in the vaccine tumor cells and not in the tumor bed and surrounding stroma where the cytokine could be readily produced and exert its immunosuppressive effects to promote tumor progression in the rats. Nevertheless, these preclinical studies led to early clinical trials showing that s.c. injections of these vaccines were well tolerated in phase I and II trials enrolling glioma patients and stage II, III, and IV lung cancer patients (77, 78). Elevated serum levels of either IFN-γ or immunoglobulins against vaccine cells were noted in some patients on these trials (77, 78). However, it was unclear whether any immune response was elicited against relevant tumor antigens. The authors reported clinical responses in vaccinated patients (77, 78), although assessment of response and clinical benefit is particularly difficult in this patient population. Therefore, larger clinical trials will be necessary to further characterize the activity of this approach.

Although TGF-β secretion from tumor cells may be important in inhibiting antitumor responses by the immune system, localized blockade of TGF-β in tumors may not be the most effective approach as several other cell types in the tumor microenvironment can produce this immunosuppressive cytokine, including Tregs and stromal cells. Systemic blockade of TGF-β via systemic administration of a small-molecule or antibody inhibitor may be more effective at enhancing antitumor responses that would be inhibited by this cytokine. To this end, monoclonal antibodies blocking TGF-β and small-molecule inhibitors of TGF-β signaling are also entering clinical trials.5,6 These approaches have shown acceptable safety profiles as well as improved antitumor activity in the preclinical studies summarized in Table 1. The results from these animal studies have led to the development of early clinical trials evaluating systemic blockade of TGF-β in cancer patients with refractory disease. A multicenter, open label, dose-escalation phase I study evaluating a monoclonal antibody, GC1008, in patients with advanced renal cell carcinoma or malignant melanoma opened last year and is accruing patients.5 Patients eligible for this study will receive up to four doses of GC1008. In addition to the antibody approach, LY573636, a small-molecule inhibitor blocking TGF-β kinase activity is currently being evaluated in clinical trials. Recently, a phase I clinical trial evaluating this small-molecule inhibitor in refractory ovarian cancer, non–small cell lung cancer, soft tissue sarcoma, and thymoma patients reported that this compound was well tolerated as a 2-h i.v. infusion administered every 21 days (80). The main dose-limiting toxicity was bone marrow suppression manifested as grade 3/4 thrombocytopenia and neutropenia (80). Subsequent phase II studies of metastatic melanoma patients6 and non–small cell lung cancer patients7 evaluating this approach are in progress.

Although systemic blockade of TGF-β has been well-tolerated in animal models, it is possible that significant toxicities including autoimmune disease will be observed in clinical trials, particularly if used in combination with other immune activators. Murine models in which TGF-β signaling is blocked in CD4+ and CD8+ lymphocytes develop autoimmune colitis as they age, suggesting that autoimmunity may be observed in patients following prolonged systemic blockade of this cytokine. Of note, antagonistic antibodies to CTLA-4, a molecule inhibiting T-cell proliferation following initial activation, have produced several autoimmune breakthrough events in advanced cancer patients, including dermatitis, enterocolitis, hypophysitis, uveitis, hepatitis, and nephritis (81). Other potential toxicities of TGF-β blockade may be related to its regulatory function in other tissues including angiogenesis and musculoskeletal development.

By understanding the roles of TGF-β in promoting tumorigenesis and developing inhibitors to selectively inhibit TGF-β during the specific time points when it promotes progression of later stages of disease, we may be able to design more effective immunotherapies augmenting the antitumor response in cancer patients. The clinical benefits from initial trials evaluating blockade of TGF-β are unclear and larger studies are necessary to determine the efficacy of these approaches. Monoclonal antibodies and small-molecule inhibitors have been evaluated in preclinical models and early clinical trials assessing systemic blockade of TGF-β signaling are in progress.

Although the preclinical murine studies discussed in this review have suggested that TGF-β blockade can enhance antitumor activity, the effect can be overcome by increased tumor burden,8 indicating that this approach will likely need to be combined with chemotherapies or other immunotherapies to effectively eradicate tumors in cancer patients. Other such strategies of this nature are being developed and are the subject of papers in this issue of Clinical Cancer Research Focus (82–85). However, the toxicities of systemic blockade of this cytokine remain unknown and may worsen with additional chemotherapies or immunotherapies. Preclinical studies evaluating combinatorial immunotherapies and chemotherapies with TGF-β blockade are under way. We anticipate that the results from these animal studies will guide future trials evaluating combinations of TGF-β blockade, immunotherapies, and chemotherapies in cancer patients.

Conclusions

Regulation of the immune response is vital to prevent the development of autoimmune diseases. As a critical immune suppressive cytokine, TGF-β has pleiotropic functions in regulating multiple immune cells in a context-dependent manner. However, dysregulation of the immunosuppressive function of TGF-β promotes tumorigenesis, particularly in later stages of cancer development. Further studies of the mechanisms and signaling pathways mediating TGF-β will lead to an improved understanding of how our immune system achieves self-tolerance and mounts effective immune responses against unsolicited foreign antigens and tumors. This knowledge may ultimately lead to the development of innovative therapeutic strategies to manipulate the effects of TGF-β on the immune system to treat cancer patients.

Acknowledgments

We thank M. Sznol for critical review and helpful comments in preparing the manuscript and F. Manzo for secretarial assistance.

Footnotes

  • Received May 10, 2007.
  • Revision received June 25, 2007.
  • Accepted July 9, 2007.

References

  1. ↵
    Li MO, Wan YY, Sanjabi S, Robertson AK, Flavell RA. Transforming growth factor-β regulation of immune responses. Annu Rev Immunol 2006;24:99–146.
    OpenUrlCrossRefPubMed
  2. ↵
    Newfeld SJ, Wisotzkey RG, Kumar S. Molecular evolution of a developmental pathway: phylogenetic analyses of transforming growth factor-β family ligands, receptors, and Smad signal transducers. Genetics 1999;152:783–95.
    OpenUrlAbstract/FREE Full Text
  3. ↵
    Kehrl JH, Wakefield LM, Roberts AB, et al. Production of transforming growth factor β by human T lymphocytes and its potential role in the regulation of T cell growth. J Exp Med 1986;163:1037–50.
    OpenUrlAbstract/FREE Full Text
  4. ↵
    Kulkarni AB, Huh CG, Becker D, et al. Transforming growth factor β1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci U S A 1993;90:770–4.
    OpenUrlAbstract/FREE Full Text
  5. ↵
    Shull MM, Ormsby I, Kier AB, et al. Targeted disruption of the mouse transforming growth factor-β1 gene results in multifocal inflammatory disease. Nature 1992;359:693–9.
    OpenUrlCrossRefPubMed
  6. ↵
    Datto MB, Frederick JP, Pan L, Borton AJ, Zhuang Y, Wang XF. Targeted disruption of Smad3 reveals an essential role in transforming growth factor β-mediated signal transduction. Mol Cell Biol 1999;19:2495–504.
    OpenUrlAbstract/FREE Full Text
  7. ↵
    Yang X, Letterio JJ, Lechleider RJ, et al. Targeted disruption of SMAD3 results in impaired mucosal immunity and diminished T cell responsiveness to TGF-β. EMBO J 1999;18:1280–91.
    OpenUrlAbstract
  8. ↵
    Cazac BB, Roes J. TGF-β receptor controls B cell responsiveness and induction of IgA in vivo. Immunity 2000;13:443–51.
    OpenUrlCrossRefPubMed
  9. ↵
    Gorelik L, Flavell RA. Abrogation of TGFβ signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity 2000;12:171–81.
    OpenUrlCrossRefPubMed
  10. ↵
    Laouar Y, Sutterwala FS, Gorelik L, Flavell RA. Transforming growth factor-β controls T helper type 1 cell development through regulation of natural killer cell interferon-γ. Nat Immunol 2005;6:600–7.
    OpenUrlCrossRefPubMed
  11. Lucas PJ, Kim SJ, Melby SJ, Gress RE. Disruption of T cell homeostasis in mice expressing a T cell-specific dominant negative transforming growth factor βII receptor. J Exp Med 2000;191:1187–96.
    OpenUrlAbstract/FREE Full Text
  12. ↵
    Nakao A, Miike S, Hatano M, et al. Blockade of transforming growth factor β/Smad signaling in T cells by overexpression of Smad7 enhances antigen-induced airway inflammation and airway reactivity. J Exp Med 2000;192:151–8.
    OpenUrlAbstract/FREE Full Text
  13. ↵
    Gorelik L, Flavell RA. Immune-mediated eradication of tumors through the blockade of transforming growth factor-β signaling in T cells. Nat Med 2001;7:1118–22.
    OpenUrlCrossRefPubMed
  14. ↵
    Chang H, Brown CW, Matzuk MM. Genetic analysis of the mammalian transforming growth factor-β superfamily. Endocr Rev 2002;23:787–823.
    OpenUrlCrossRefPubMed
  15. ↵
    Govinden R, Bhoola KD. Genealogy, expression, and cellular function of transforming growth factor-β. Pharmacol Ther 2003;98:257–65.
    OpenUrlCrossRefPubMed
  16. ↵
    Dubois CM, Laprise MH, Blanchette F, Gentry LE, Leduc R. Processing of transforming growth factor β1 precursor by human furin convertase. J Biol Chem 1995;270:10618–24.
    OpenUrlAbstract/FREE Full Text
  17. ↵
    Annes JP, Chen Y, Munger JS, Rifkin DB. Integrin αVβ6-mediated activation of latent TGF-β requires the latent TGF-β binding protein-1. J Cell Biol 2004;165:723–34.
    OpenUrlAbstract/FREE Full Text
  18. Annes JP, Munger JS, Rifkin DB. Making sense of latent TGFβ activation. J Cell Sci 2003;116:217–24.
    OpenUrlAbstract/FREE Full Text
  19. Crawford SE, Stellmach V, Murphy-Ullrich JE, et al. Thrombospondin-1 is a major activator of TGF-β1 in vivo. Cell 1998;93:1159–70.
    OpenUrlCrossRefPubMed
  20. Munger JS, Huang X, Kawakatsu H, et al. The integrin αvβ6 binds and activates latent TGF β1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 1999;96:319–28.
    OpenUrlCrossRefPubMed
  21. ↵
    Yehualaeshet T, O'Connor R, Green-Johnson J, et al. Activation of rat alveolar macrophage-derived latent transforming growth factor β-1 by plasmin requires interaction with thrombospondin-1 and its cell surface receptor, CD36. Am J Pathol 1999;155:841–51.
    OpenUrlCrossRefPubMed
  22. ↵
    Padgett RW, Cho S-H, Evangelista C. Smads are the central component in transforming growth factor-β signaling. Pharmacol Ther 1998;78:47–52.
    OpenUrlCrossRefPubMed
  23. Huse M, Muir TW, Xu L, Chen YG, Kuriyan J, Massague J. The TGFβ receptor activation process: an inhibitor- to substrate-binding switch. Mol Cell 2001;8:671–82.
    OpenUrlCrossRefPubMed
  24. Massague J. TGF-β signal transduction. Annu Rev Biochem 1998;67:753–91.
    OpenUrlCrossRefPubMed
  25. ↵
    Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-β family signalling. Nature 2003;425:577–84.
    OpenUrlCrossRefPubMed
  26. ↵
    Massague J, Gomis RR. The logic of TGF[β] signaling. FEBS Lett Istanbul Special Issue 2006;580:2811–20.
    OpenUrl
  27. ↵
    Thomas DA, Massague J. TGF-[β] directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell 2005;8:369–80.
    OpenUrlCrossRefPubMed
  28. ↵
    Dudley ME, Wunderlich JR, Yang JC, et al. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol 2005;23:2346–57.
    OpenUrlAbstract/FREE Full Text
  29. ↵
    Mende I, Engleman EG. Breaking tolerance to tumors with dendritic cell-based immunotherapy. Ann N Y Acad Sci 2005;1058:96–104.
    OpenUrlCrossRefPubMed
  30. ↵
    Ma A, Koka R, Burkett P. Diverse functions of IL-2, IL-15, and IL-7 in lymphoid homeostasis. Annu Rev Immunol 2006;24:657–79.
    OpenUrlCrossRefPubMed
  31. ↵
    Becknell B, Caligiuri MA, Frederick WA. Interleukin-2, interleukin-15, and their roles in human natural killer cells. Adv Immunol 2005;86:209–39.
    OpenUrlCrossRefPubMed
  32. ↵
    Brabletz T, Pfeuffer I, Schorr E, Siebelt F, Wirth T, Serfling E. Transforming growth factor β and cyclosporin A inhibit the inducible activity of the interleukin-2 gene in T cells through a noncanonical octamer-binding site. Mol Cell Biol 1993;13:1155–62.
    OpenUrlAbstract/FREE Full Text
  33. ↵
    McKarns SC, Schwartz RH, Kaminski NE. Smad3 is essential for TGF-β1 to suppress IL-2 production and TCR-induced proliferation, but not IL-2-induced proliferation. J Immunol 2004;172:4275–84.
    OpenUrlAbstract/FREE Full Text
  34. ↵
    Coffey RJ, Jr., Bascom CC, Sipes NJ, Graves-Deal R, Weissman BE, Moses HL. Selective inhibition of growth-related gene expression in murine keratinocytes by transforming growth factor β. Mol Cell Biol 1988;8:3088–93.
    OpenUrlAbstract/FREE Full Text
  35. Datto MB, Li Y, Panus JF, Howe DJ, Xiong Y, Wang XF. Transforming growth factor β induces the cyclin-dependent kinase inhibitor p21 through a p53-independent mechanism. Proc Natl Acad Sci U S A 1995;92:5545–9.
    OpenUrlAbstract/FREE Full Text
  36. Hannon GJ, Beach D. p15INK4B is a potential effector of TGF-β-induced cell cycle arrest. Nature 1994;371:257–61.
    OpenUrlCrossRefPubMed
  37. Polyak K, Kato JY, Solomon MJ, et al. p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-β and contact inhibition to cell cycle arrest. Genes Dev 1994;8:9–22.
    OpenUrlAbstract/FREE Full Text
  38. Ruegemer JJ, Ho SN, Augustine JA, et al. Regulatory effects of transforming growth factor-β on IL-2- and IL-4-dependent T cell-cycle progression. J Immunol 1990;144:1767–76.
    OpenUrlAbstract/FREE Full Text
  39. ↵
    Wolfraim LA, Walz TM, James Z, Fernandez T, Letterio JJ. p21Cip1 and p27Kip1 act in synergy to alter the sensitivity of naive T cells to TGF-β-mediated G1 arrest through modulation of IL-2 responsiveness. J Immunol 2004;173:3093–102.
    OpenUrlAbstract/FREE Full Text
  40. ↵
    Ahmadzadeh M, Rosenberg SA. TGF-β1 attenuates the acquisition and expression of effector function by tumor antigen-specific human memory CD8 T cells. J Immunol 2005;174:5215–23.
    OpenUrlAbstract/FREE Full Text
  41. Bonig H, Banning U, Hannen M, et al. Transforming growth factor-β1 suppresses interleukin-15-mediated interferon-γ production in human T lymphocytes. Scand J Immunol 1999;50:612–8.
    OpenUrlCrossRefPubMed
  42. Ranges GE, Figari IS, Espevik T, Palladino MA, Jr. Inhibition of cytotoxic T cell development by transforming growth factor β and reversal by recombinant tumor necrosis factor α. J Exp Med 1987;166:991–8.
    OpenUrlAbstract/FREE Full Text
  43. ↵
    Smyth MJ, Strobl SL, Young HA, Ortaldo JR, Ochoa AC. Regulation of lymphokine-activated killer activity and pore-forming protein gene expression in human peripheral blood CD8+ T lymphocytes. Inhibition by transforming growth factor-β. J Immunol 1991;146:3289–97.
    OpenUrlAbstract/FREE Full Text
  44. ↵
    Mempel TR, Pittet MJ, Khazaie K, et al. Regulatory T cells reversibly suppress cytotoxic T cell function independent of effector differentiation. Immunity 2006;25:129–41.
    OpenUrlCrossRefPubMed
  45. ↵
    Rudner LA, Lin JT, Park IK, et al. Necroinflammatory liver disease in BALB/c background, TGF-β1-deficient mice requires CD4+ T cells. J Immunol 2003;170:4785–92.
    OpenUrlAbstract/FREE Full Text
  46. ↵
    Zhang Q, Jang TL, Yang X, et al. Infiltration of tumor-reactive transforming growth factor-β insensitive CD8+ T cells into the tumor parenchyma is associated with apoptosis and rejection of tumor cells. Prostate 2006;66:235–47.
    OpenUrlCrossRefPubMed
  47. ↵
    Lopez M, Aguilera R, Perez C, et al. The role of regulatory T lymphocytes in the induced immune response mediated by biological vaccines. Immunobiology 2006;211:127–36.
    OpenUrlCrossRefPubMed
  48. ↵
    Li MO, Sanjabi S, Flavell RA. Transforming growth factor-β controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms. Immunity 2006;25:455–71.
    OpenUrlCrossRefPubMed
  49. ↵
    Mamura M, Lee W, Sullivan TJ, et al. CD28 disruption exacerbates inflammation in Tgf-β1−/− mice: in vivo suppression by CD4+CD25+ regulatory T cells independent of autocrine TGF-β1. Blood 2004;103:4594–601.
    OpenUrlAbstract/FREE Full Text
  50. ↵
    Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 2005;22:329–41.
    OpenUrlCrossRefPubMed
  51. ↵
    Wan YY, Flavell RA. Identifying Foxp3-expressing suppressor T cells with a bicistronic reporter. Proc Natl Acad Sci U S A 2005;102:5126–31.
    OpenUrlAbstract/FREE Full Text
  52. ↵
    Rook AH, Kehrl JH, Wakefield LM, et al. Effects of transforming growth factor β on the functions of natural killer cells: depressed cytolytic activity and blunting of interferon responsiveness. J Immunol 1986;136:3916–20.
    OpenUrlAbstract
  53. ↵
    Bellone G, Aste-Amezaga M, Trinchieri G, Rodeck U. Regulation of NK cell functions by TGF-β1. J Immunol 1995;155:1066–73.
    OpenUrlAbstract/FREE Full Text
  54. ↵
    Moretta A, Biassoni R, Bottino C, Mingari MC, Moretta L. Natural cytotoxicity receptors that trigger human NK-cell-mediated cytolysis. Immunol Today 2000;21:228–34.
    OpenUrlCrossRefPubMed
  55. ↵
    Bauer S, Groh V, Wu J, et al. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 1999;285:727–9.
    OpenUrlAbstract/FREE Full Text
  56. ↵
    Castriconi R, Cantoni C, Della Chiesa M, et al. Transforming growth factor β1 inhibits expression of NKp30 and NKG2D receptors: consequences for the NK-mediated killing of dendritic cells. Proc Natl Acad Sci U S A 2003;100:4120–5.
    OpenUrlAbstract/FREE Full Text
  57. ↵
    Lee J-C, Lee K-M, Kim D-W, Heo DS. Elevated TGF-β1 secretion and down-modulation of NKG2D underlies impaired NK cytotoxicity in cancer patients. J Immunol 2004;172:7335–40.
    OpenUrlAbstract/FREE Full Text
  58. ↵
    Fong L, Engleman EG. Dendritic cells in cancer immunotherapy. Annu Rev Immunol 2000;18:245–73.
    OpenUrlCrossRefPubMed
  59. ↵
    Geissmann F, Revy P, Regnault A, et al. TGF-β1 prevents the noncognate maturation of human dendritic Langerhans cells. J Immunol 1999;162:4567–75.
    OpenUrlAbstract/FREE Full Text
  60. ↵
    Teicher BA. Malignant cells, directors of the malignant process: role of transforming growth factor-β. Cancer Metastasis Rev 2001;20:133–43.
    OpenUrlCrossRefPubMed
  61. ↵
    Dong M, Blobe GC. Role of transforming growth factor-β in hematologic malignancies. Blood 2006;107:4589–96.
    OpenUrlAbstract/FREE Full Text
  62. ↵
    Levy L, Hill CS. Alterations in components of the TGF-β superfamily signaling pathways in human cancer. Cytokine Growth Factor Rev 2006;17:41–58.
    OpenUrlCrossRefPubMed
  63. ↵
    Chang HL, Gillett N, Figari I, Lopez AR, Palladino MA, Derynck R. Increased transforming growth factor β expression inhibits cell proliferation in vitro, yet increases tumorigenicity and tumor growth of Meth A sarcoma cells. Cancer Res 1993;53:4391–8.
    OpenUrlAbstract/FREE Full Text
  64. ↵
    Grady WM, Myeroff LL, Swinler SE, et al. Mutational inactivation of transforming growth factor β receptor type II in microsatellite stable colon cancers. Cancer Res 1999;59:320–4.
    OpenUrlAbstract/FREE Full Text
  65. ↵
    Maurice D, Pierreux CE, Howell M, Wilentz RE, Owen MJ, Hill CS. Loss of Smad4 function in pancreatic tumors. C-terminal truncation leads to decreased stability. J Biol Chem 2001;276:43175–81.
    OpenUrlAbstract/FREE Full Text
  66. ↵
    Galliher A, Schiemann W. β3 Integrin and Src facilitate transforming growth factor-β mediated induction of epithelial-mesenchymal transition in mammary epithelial cells. Breast Cancer Res 2006;8:R42.
    OpenUrlCrossRefPubMed
  67. ↵
    Blobe GC, Schiemann WP, Lodish HF. Role of transforming growth factor β in human disease. N Engl J Med 2000;342:1350–8.
    OpenUrlCrossRefPubMed
  68. ↵
    Dalal BI KP, Greenberg AH. Immunocytochemical localization of secreted transforming growth factor-β1 to the advancing edges of primary tumors and to lymph node metastases of human mammary carcinoma. Am J Pathol 1993;143:381–9.
    OpenUrlPubMed
  69. ↵
    Picon A, Gold LI, Wang J, Cohen A, Friedman E. A subset of metastatic human colon cancers expresses elevated levels of transforming growth factor β1. Cancer Epidemiol Biomarkers Prev 1998;7:497–504.
    OpenUrlAbstract/FREE Full Text
  70. ↵
    Saito H TS, Oka S, Kondo A, Ikeguchi M, Maeta M, Kaibara N. An elevated serum level of transforming growth factor-β1 (TGF-β1) significantly correlated with lymph node metastasis and poor prognosis in patients with gastric carcinoma. Anticancer Res 2000;20:4489–93.
    OpenUrlPubMed
  71. ↵
    Friedman E, Gold LI, Klimstra D, Zeng ZS, Winawer S, Cohen A. High levels of transforming growth factor β1 correlate with disease progression in human colon cancer. Cancer Epidemiol Biomarkers Prev 1995;4:549–54.
    OpenUrlAbstract
  72. Gorsch S, Memoli V, Stukel T, et al. Immunohistochemical staining for transforming growth factor β1 associates with disease progression in human breast cancer. Cancer Res 1992;52:6949–52.
    OpenUrlAbstract/FREE Full Text
  73. ↵
    Takanami I, Tanaka F, Hashizume T, et al. Roles of the transforming growth factor β-1 and its type I and II receptors in the development of a pulmonary adenocarcinoma: results of an immunohistochemical study. J Surg Oncol 1997;64:262–7.
    OpenUrlCrossRefPubMed
  74. ↵
    Torre-Amione G, Beauchamp RD, Koeppen H, et al. A highly immunogenic tumor transfected with a murine transforming growth factor type β1 cDNA escapes immune surveillance. Proc Natl Acad Sci U S A 1990;87:1486–90.
    OpenUrlAbstract/FREE Full Text
  75. ↵
    Curiel TJ, Coukos G, Zou L, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 2004;10:942–9.
    OpenUrlCrossRefPubMed
  76. ↵
    Schlingensiepen K-H, Schlingensiepen R, Steinbrecher A, et al. Targeted tumor therapy with the TGF-β2 antisense compound AP 12009. Cytokine Growth Factor Rev 2006;17:129–39.
    OpenUrlCrossRefPubMed
  77. ↵
    Fakhrai H, Mantil JC, Liu L, et al. Phase I clinical trial of a TGF-β antisense-modified tumor cell vaccine in patients with advanced glioma. Cancer Gene Ther 2006;13:1052–60.
    OpenUrlCrossRefPubMed
  78. ↵
    Nemunaitis J, Dillman RO, Schwarzenberger PO, et al. Phase II study of belagenpumatucel-L, a transforming growth factor β-2 antisense gene-modified allogeneic tumor cell vaccine in non-small-cell lung cancer. J Clin Oncol 2006;24:4721–30.
    OpenUrlAbstract/FREE Full Text
  79. ↵
    Fakhrai H, Dorigo O, Shawler DL, et al. Eradication of established intracranial rat gliomas by transforming growth factor β antisense gene therapy. Proc Natl Acad Sci U S A 1996;93:2909–14.
    OpenUrlAbstract/FREE Full Text
  80. ↵
    Ilaria RL, Simon GR, Sovak M, et al. Spriggs Phase I study of LY573636-sodium, an acylsulfonamide anti-cancer compound with a novel mechanism of action, administered as 2-hour IV infusion in patients with advanced solid tumors. ASCO Annual Meeting Proceeding Part I. J Clin Oncol 2007;25:2515.
    OpenUrl
  81. ↵
    Beck KE, Blansfield JA, Tran KQ, et al. Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4. J Clin Oncol 2006;24:2283–9.
    OpenUrlAbstract/FREE Full Text
  82. ↵
    Lizée G, Cantu MA, Hwu P. Less ying, more yang: confronting the barriers to cancer immunotherapy. Clin Cancer Res 2007;13:5250–5.
    OpenUrlAbstract/FREE Full Text
  83. Paulos CM, Kaiser A, Wrzesinski C, et al. Toll-like receptors in tumor immunotherapy. Clin Cancer Res 2007;13:5280–90.
    OpenUrlAbstract/FREE Full Text
  84. Zang X, Allison JP. The B7 family and cancer therapy: costimulation and coinhibition. Clin Cancer Res 2007;13:5271–9.
    OpenUrlAbstract/FREE Full Text
  85. ↵
    Gajewski T. Failure at the effector phase: immune barriers at the level of the melanoma tumor microenvironment. Clin Cancer Res 2007;13:5256–61.
    OpenUrlAbstract/FREE Full Text
  86. ↵
    Schlingensiepen R, Goldbrunner M, Szyrach MNI, et al. Intracerebral and intrathecal infusion of the TGF-β2-specific antisense phosphorothioate oligonucleotide AP 12009 in rabbits and primates: toxicology and safety. Oligonucleotides 2005;15:94–104.
    OpenUrlCrossRefPubMed
  87. ↵
    Saunier EF, Akhurst RJ. TGFβ inhibition for cancer therapy. Curr Cancer Drug Targets 2006;6:565–78.
    OpenUrlCrossRefPubMed
  88. ↵
    Mead AL, Wong TTL, Cordeiro MF, Anderson IK, Khaw PT. Evaluation of anti-TGF-β2 antibody as a new postoperative anti-scarring agent in glaucoma surgery. Invest Ophthalmol Vis Sci 2003;44:3394–401.
    OpenUrlAbstract/FREE Full Text
  89. ↵
    Benigni A, Zoja C, Corna D, et al. Add-on anti-TGF-β antibody to ACE inhibitor arrests progressive diabetic nephropathy in the rat. J Am Soc Nephrol 2003;14:1816–24.
    OpenUrlAbstract/FREE Full Text
  90. ↵
    Nam J-S, Suchar AM, Kang M-J, et al. Bone sialoprotein mediates the tumor cell-targeted prometastatic activity of transforming growth factor β in a mouse model of breast cancer. Cancer Res 2006;66:6327–35.
    OpenUrlAbstract/FREE Full Text
  91. ↵
    Yingling JM, Blanchard KL, Sawyer JS. Development of TGF-β signalling inhibitors for cancer therapy. Nat Rev Drug Discov 2004;3:1011–22.
    OpenUrlCrossRefPubMed
  92. Scott Sawyer J, Beight DW, Britt KS, et al. Synthesis and activity of new aryl- and heteroaryl-substituted 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole inhibitors of the transforming growth factor-β type I receptor kinase domain. Bioorg Med Chem Lett 2004;14:3581–4.
    OpenUrlCrossRefPubMed
  93. ↵
    Kano MR, Bae Y, Iwata C, et al. Improvement of cancer-targeting therapy, using nanocarriers for intractable solid tumors by inhibition of TGF-β signaling. Proc Natl Acad Sci U S A 2007;104:3460–5.
    OpenUrlAbstract/FREE Full Text
  94. ↵
    Inman GJ, Nicolas FJ, Callahan JF, et al. SB-431542 is a potent and specific inhibitor of transforming growth factor-β superfamily type I activin receptor-like kinase (ALK) receptors ALK4, ALK5, and ALK7. Mol Pharmacol 2002;62:65–74.
    OpenUrlAbstract/FREE Full Text
  95. ↵
    Hayashi T, Hideshima T, Nguyen AN, et al. Transforming growth factor β receptor I kinase inhibitor down-regulates cytokine secretion and multiple myeloma cell growth in the bone marrow microenvironment. Clin Cancer Res 2004;10:7540–6.
    OpenUrlAbstract/FREE Full Text
  96. ↵
    Uhl M, Aulwurm S, Wischhusen J, et al. SD-208, a novel transforming growth factor β receptor I kinase inhibitor, inhibits growth and invasiveness and enhances immunogenicity of murine and human glioma cells in vitro and in vivo. Cancer Res 2004;64:7954–61.
    OpenUrlAbstract/FREE Full Text
  97. ↵
    Ehata S, Hanyu A, Fujime M, et al. Ki26894, a novel transforming growth factor-β type I receptor kinase inhibitor, inhibits in vitro invasion and in vivo bone metastasis of a human breast cancer cell line. Cancer Sci 2007;98:127–33.
    OpenUrlCrossRefPubMed
  98. ↵
    Suzuki E, Kim S, Cheung HK, et al. A novel small-molecule inhibitor of transforming growth factor β type I receptor kinase (SM16) inhibits murine mesothelioma tumor growth in vivo and prevents tumor recurrence after surgical resection. Cancer Res 2007;67:2351–9.
    OpenUrlAbstract/FREE Full Text
  99. ↵
    Qiqi C, Sang Kyun L, Bryan Z, Michael Hoffmann F. Selective inhibition of TGF-β responsive genes by Smad-interacting peptide aptamers from FoxH1, Lef1, and CBP. Oncogene 2005;24:3864–74.
    OpenUrlCrossRefPubMed
  100. ↵
    Yang Y-a, Dukhanina O, Tang B, et al. Lifetime exposure to a soluble TGF-β antagonist protects mice against metastasis without adverse side effects. J Clin Invest 2002;109:1607–15.
    OpenUrlCrossRefPubMed
Back to top
Clinical Cancer Research: 13 (18)
September 2007
Volume 13, Issue 18

Sign up for alerts

View this article with LENS

Open full page PDF
Article Alerts
Email Article
Citation Tools
Transforming Growth Factor-β and the Immune Response: Implications for Anticancer Therapy
Stephen H. Wrzesinski, Yisong Y. Wan and Richard A. Flavell
Clin Cancer Res September 15 2007 (13) (18) 5262-5270; DOI: 10.1158/1078-0432.CCR-07-1157
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo

Jump to section

Advertisement