Advertisement

A Role for STAT3 in Dendritic Cell Regulation by Tumor-Derived Factors

  • Dmitry I. Gabrilovich
Chapter

Abstract

Ineffective dendritic cell differentiation and activation in cancer is a well-established phenomenon that is considered as one of the major mechanisms of tumor escape. The defects in dendritic cells are caused primarily by soluble tumor-derived factors. In recent years accumulated evidence suggested that the members of the family of signal transducers and activators of transcription (STAT), and more specifically STAT3, could be primarily responsible for dendritic cell defects in cancer. In this review we will discuss recent findings describing the role of STAT3 in dendritic cell differentiation and function.

Keywords

Dendritic Cell Mature Dendritic Cell Dendritic Cell Differentiation Dendritic Cell Development Metastatic Human Pancreatic Cancer Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Albert, M. L., Birthe, S. and Bhardwaj, N. 1998. Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs. Nature 392:86–89.PubMedCrossRefGoogle Scholar
  2. Alexander, W. S., Starr, R., Metcalf, D., Nicholson, S. E., Farley, A., Elefanty, A. G., Brysha, M., Kile, B. T., Richardson, R., Baca, M., Zhang, J. G., Willson, T. A., Viney, E. M., Sprigg, N. S., Rakar, S., Corbin, J., Mifsud, S., DiRago, L., Cary, D., Nicola, N. A. and Hilton, D. J. 1999. Suppressors of cytokine signaling (SOCS): negative regulators of signal transduction. J Leukoc Biol 66:588–592.PubMedGoogle Scholar
  3. Bharadwaj, U., Li, M., Zhang, R., Chen, C. and Yao, Q. 2007. Elevated interleukin-6 and G-CSF in human pancreatic cancer cell conditioned medium suppress dendritic cell differentiation and activation. Cancer Res 67:5479–5488.PubMedCrossRefGoogle Scholar
  4. Blaskovich, M. A., Sun, J., Cantor, A., Turkson, J., Jove, R. and Sebti, S. M. 2003. Discovery of JSI-124 (Cucurbitacin I), a selective janus kinase/signal transducer and activator of transcription 3 signaling pathway inhibitor with potent antitumor activity against human and murine cancer cells in mice. Cancer Res 63:1270–1279.PubMedGoogle Scholar
  5. Bromberg, J. 2002. Stat proteins and oncogenesis. J Clin Invest 109:1139–1142.PubMedGoogle Scholar
  6. Calo, V., Migliavacca, M., Bazan, V., Macaluso, M., Buscemi, M., Gebbia, N. and Russo, A. 2003. STAT proteins: from normal control of cellular events to tumorigenesis. J Cell Physiol 197:157–168.PubMedCrossRefGoogle Scholar
  7. Cheng, F., Wang, H. W., Cuenca, A., Huang, M., Ghansah, T., Brayer, J., Kerr, W. G., Takeda, K., Akira, S., Schoenberger, S. P., Yu, H., Jove, R. and Sotomayor, E. M. 2003. A critical role for Stat3 signaling in immune tolerance. Immunity 19:425–436.PubMedCrossRefGoogle Scholar
  8. Chung, J., Uchida, E., Grammer, T. C. and Blenis, J. 1997. STAT3 serine phosphorylation by ERK-dependent and -independent pathways negatively modulates its tyrosine phosphorylation. Mol Cell Biol 17:6508–6516.PubMedGoogle Scholar
  9. Coffer, P. J., Koenderman, L. and de Groot, R. P. 2000. The role of STATs in myeloid differentiation and leukemia. Oncogene 19:2511–2522.PubMedCrossRefGoogle Scholar
  10. Dalpke, A. H., Opper, S., Zimmermann, S. and Heeg, K. 2001. Suppressors of cytokine signaling (SOCS)-1 and SOCS-3 are induced by CpG-DNA and modulate cytokine responses in APCs. J Immunol 166:7082–7089.PubMedGoogle Scholar
  11. Darnell, J. E., Jr. 1997. STATs and gene regulation. Science 277:1630–1635.PubMedCrossRefGoogle Scholar
  12. Darnell, J. E., Jr., Kerr, I. M. and Stark, G. R. 1994. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264:1415–1421.PubMedCrossRefGoogle Scholar
  13. Evel-Kabler, K., Song, X. T., Aldrich, M., Huang, X. F. and Chen, S. Y. 2006. SOCS1 restricts dendritic cells' ability to break self tolerance and induce antitumor immunity by regulating IL-12 production and signaling. J Clin Invest 116:90–100.PubMedCrossRefGoogle Scholar
  14. Fujita, M., Zhu, X., Sasaki, K., Ueda, R., Low, K. L., Pollack, I. F. and Okada, H. 2008. Inhibition of STAT3 promotes the efficacy of adoptive transfer therapy using type-1 CTLs by modulation of the immunological microenvironment in a murine intracranial glioma. J Immunol 180:2089–2098.PubMedGoogle Scholar
  15. Gabrilovich, D., Ciernik, F. and Carbone, D. P. 1996. Dendritic cells in anti-tumor immune responses. I. Defective antigen presentation in tumor-bearing hosts. Cell. Immunol 170:101–110.PubMedCrossRefGoogle Scholar
  16. Gabrilovich, D. I. 2004. The mechanisms and functional significance of tumour-induced dendritic-cell defects. Nat Rev Immunol 4:941–952.PubMedCrossRefGoogle Scholar
  17. Gabrilovich, D. I., Corak, J., Ciernik, I. F., Kavanaugh, D. and Carbone, D. P. 1997. Decreased antigen presentation by dendritic cells in patients with breast cancer. Clin Cancer Res. 3:483–490.PubMedGoogle Scholar
  18. Greenhalgh, C. J. and Hilton, D. J. 2001. Negative regulation of cytokine signaling. J Leukoc Biol 70:348–356.PubMedGoogle Scholar
  19. Greenhalgh, C. J., Rico-Bautista, E., Lorentzon, M., Thaus, A. L., Morgan, P. O., Willson, T. A., Zervoudakis, P., Metcalf, D., Street, I., Nicola, N. A., Nash, A. D., Fabri, L. J., Norstedt, G., Ohlsson, C., Flores-Morales, A., Alexander, W. S. and Hilton, D. J. 2005. SOCS2 negatively regulates growth hormone action in vitro and in vivo. J Clin Invest 115:397–406.PubMedGoogle Scholar
  20. Hoentjen, F., Sartor, R. B., Ozaki, M. and Jobin, C. 2005. STAT3 regulates NF-{kappa}B recruitment to the IL-12p40 promoter in dendritic cells. Blood 105:689–696.PubMedCrossRefGoogle Scholar
  21. Huang, A. Y., Golumbek, P., Ahmadzadeh, M., Jaffee, E., Pardoll, D. and Levitsky, H. 1994. Role of bone marrow-derived cells in presenting MHC class I-restricted tumor antigens. Science 264:961–965.PubMedCrossRefGoogle Scholar
  22. Ihle, J. N. 1995. The Janus protein tyrosine kinases in hematopoietic cytokine signaling. Semin Immunol 7:247–254.PubMedCrossRefGoogle Scholar
  23. Imada, K. and Leonard, W. J. 2000. The JAK-STAT pathway. Mol Immunol 37:1–11.PubMedCrossRefGoogle Scholar
  24. Inaba, K., Turley, S., Yamaide, F., Iyoda, T., Mahnke, K., Inaba, M., Pack, M., Subklewe, M., Sauter, B., Sheff, D., Albert, M., Bhardwaj, N., Mellman, I. and Steinman, R. M. 1998. Efficient presentation of phagocytosed cellular fragments on the major histocompatibility complex class II products of dendritic cells. J Exp Med 188:2163–2173.PubMedCrossRefGoogle Scholar
  25. Jackson, S. H., Yu, C. R., Mahdi, R. M., Ebong, S. and Egwuagu, C. E. 2004. Dendritic cell maturation requires STAT1 and is under feedback regulation by suppressors of cytokine signaling. J Immunol 172:2307–2315.PubMedGoogle Scholar
  26. Kitamura, H., Kamon, H., Sawa, S., Park, S. J., Katunuma, N., Ishihara, K., Murakami, M. and Hirano, T. 2005. IL-6-STAT3 controls intracellular MHC class II alphabeta dimer level through cathepsin S activity in dendritic cells. Immunity 23:491–502.PubMedCrossRefGoogle Scholar
  27. Kortylewski, M., Kujawski, M., Wang, T., Wei, S., Zhang, S., Pilon-Thomas, S., Niu, G., Kay, H., Mule, J., Kerr, W. G., Jove, R., Pardoll, D. and Yu, H. 2005. Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat Med 11:1314–1321.PubMedCrossRefGoogle Scholar
  28. Kusmartsev, S. and Gabrilovich, D. 2005. STAT1 signaling regulates tumor-associated macrophage-mediated T cell deletion. J Immunol 174:4880–4891.PubMedGoogle Scholar
  29. Laouar, Y., Welte, T., Fu, X.-Y. and Flavell, R. A. 2003. STAT3 Is required for Flt3L-dependent dendritic cell differentiation. Immunity 19:903–912.PubMedCrossRefGoogle Scholar
  30. Levy, C., Nechushtan, H. and Razin, E. 2002. A new role for the STAT3 inhibitor, PIAS3: a repressor of microphthalmia transcription factor. J Biol Chem 277:1962–1966.PubMedCrossRefGoogle Scholar
  31. Li, Y., Chu, N., Rostami, A. and Zhang, G. X. 2006. Dendritic cells transduced with SOCS-3 exhibit a tolerogenic/DC2 phenotype that directs type 2 Th cell differentiation in vitro and in vivo. J Immunol 177:1679–1688.PubMedGoogle Scholar
  32. Liao, J., Fu, Y. and Shuai, K. 2000. Distinct roles of the NH2- and COOH-terminal domains of the protein inhibitor of activated signal transducer and activator of transcription (STAT) 1 (PIAS1) in cytokine-induced PIAS1-Stat1 interaction. Proc Natl Acad Sci USA 97:5267–5272.PubMedCrossRefGoogle Scholar
  33. Ling, X., Konopleva, M., Zeng, Z., Ruvolo, V., Stephens, L. C., Schober, W., McQueen, T., Dietrich, M., Madden, T. L. and Andreeff, M. 2007. The novel triterpenoid C-28 methyl ester of 2-cyano-3, 12-dioxoolen-1, 9-dien-28-oic acid inhibits metastatic murine breast tumor growth through inactivation of STAT3 signaling.Google Scholar
  34. Cancer Res 67:4210–4218.Google Scholar
  35. Molavi, O., Ma, Z., Hamdy, S., Lai, R., Lavasanifar, A. and Samuel, J. 2008 Synergistic antitumor effects of CpG oligodeoxynucleotide and STAT3 inhibitory agent JSI-124 in a mouse melanoma tumor model. Immunol Cell Biol Apr 8 [Epub ahead of print].Google Scholar
  36. Nadiminty, N., Lou, W., Lee, S. O., Lin, X., Trump, D. L. and Gao, A. C. 2006. Stat3 activation of NF-{kappa}B p100 processing involves CBP/p300-mediated acetylation. Proc Natl Acad Sci USA 103:7264–7269.PubMedCrossRefGoogle Scholar
  37. Nefedova, Y., Cheng, P., Gilkes, D., Blaskovich, M., Beg, A. A., Sebti, S. M. and Gabrilovich, D. I. 2005a. Activation of dendritic cells via inhibition of Jak2/STAT3 signaling. J Immunol 175:4338–4346.PubMedGoogle Scholar
  38. Nefedova, Y., Huang, M., Kusmartsev, S., Bhattacharya, R., Cheng, P., Salup, R., Jove, R. and Gabrilovich, D. 2004. Hyperactivation of STAT3 is involved in abnormal differentiation of dendritic cells in cancer. J Immunol 172:464–474.PubMedGoogle Scholar
  39. Nefedova, Y., Nagaraj, S., Rosenbauer, A., Muro-Cacho, C., Sebti, S. M. and Gabrilovich, D. I. 2005b. Regulation of dendritic cell differentiation and antitumor immune response in cancer by pharmacologic-selective inhibition of the janus-activated kinase 2/signal transducers and activators of transcription 3 pathway. Cancer Res 65:9525–9535.PubMedCrossRefGoogle Scholar
  40. Nestle, F. O., Burg, G., Fah, J., Wrone-Smith, T. and Nickoloff, B. J. 1997. Human sunlight-induced basal-cell-carcinoma-associated dendritic cells are deficient in T cell co-stimulatory molecules and are impaired as antigen-presenting cells. Am J Pathol 150:641–651.PubMedGoogle Scholar
  41. Onai, N., Obata-Onai, A., Tussiwand, R., Lanzavecchia, A. and Manz, M. G. 2006. Activation of the Flt3 signal transduction cascade rescues and enhances type I interferon-producing and dendritic cell development. J Exp Med 203:227–238.PubMedCrossRefGoogle Scholar
  42. Park, S. J., Nakagawa, T., Kitamura, H., Atsumi, T., Kamon, H., Sawa, S., Kamimura, D., Ueda, N., Iwakura, Y., Ishihara, K., Murakami, M. and Hirano, T. 2004. IL-6 regulates in vivo dendritic cell differentiation through STAT3 activation. J Immunol 173:3844–3854.PubMedGoogle Scholar
  43. Rane, S. G. and Reddy, E. P. 2002. JAKs, STATs and Src kinases in hematopoiesis. Oncogene 21:3334–3358.PubMedCrossRefGoogle Scholar
  44. Rane, S. G. and Reddy, E. S. 2000. Janus kinases: components of multiple signaling pathways. Oncogene 19:5662–5679.PubMedCrossRefGoogle Scholar
  45. Rathinam, C., Geffers, R., Yucel, R., Buer, J., Welte, K., Moroy, T. and Klein, C. 2005. The transcriptional repressor Gfi1 controls STAT3-dependent dendritic cell development and function. Immunity 22:717–728.PubMedCrossRefGoogle Scholar
  46. Rock, K. L., Rothstein, L., Gamble, S. and Fleischacker, C. 1993. Characterization of antigen-presenting cells that present exogenous antigens in association with class I MHC molecules. J Immunol 150:438–446.PubMedGoogle Scholar
  47. Schaper, F., Gendo, C., Eck, M., Schmitz, J., Grimm, C., Anhuf, D., Kerr, I. M. and Heinrich, P. C. 1998. Activation of the protein tyrosine phosphatase SHP2 via the interleukin-6 signal transducing receptor protein gp130 requires tyrosine kinase Jak1 and limits acute-phase protein expression. Biochem J 335(Pt 3):557–565.PubMedGoogle Scholar
  48. Shen, L., Evel-Kabler, K., Strube, R. and Chen, S. Y. 2004. Silencing of SOCS1 enhances antigen presentation by dendritic cells and antigen-specific anti-tumor immunity. Nat Biotechnol 22:1546–1553.PubMedCrossRefGoogle Scholar
  49. Shuai, K. and Liu, B. 2003. Regulation of JAK-STAT signalling in the immune system. Nat Rev Immunol 3:900–911.PubMedCrossRefGoogle Scholar
  50. Shuai, K. and Liu, B. 2005. Regulation of gene-activation pathways by PIAS proteins in the immune system. Nat Rev Immunol 5:593–605.PubMedCrossRefGoogle Scholar
  51. Shurin, M. and Gabrilovich, D. I. 2001. Regulation of dendritic cell system by tumor. Cancer Res Ther Control 11:65–78.Google Scholar
  52. Smithgall, T. E., Briggs, S. D., Schreiner, S., Lerner, E. C., Cheng, H. and Wilson, M. B. 2000. Control of myeloid differentiation and survival by Stats. Oncogene 19:2612–2618.PubMedCrossRefGoogle Scholar
  53. Starr, R., Willson, T. A., Viney, E. M., Murray, L. J., Rayner, J. R., Jenkins, B. J., Gonda, T. J., Alexander, W. S., Metcalf, D., Nicola, N. A. and Hilton, D. J. 1997. A family of cytokine-inducible inhibitors of signalling. Nature 387:917–921.PubMedCrossRefGoogle Scholar
  54. Stofega, M. R., Wang, H., Ullrich, A. and Carter-Su, C. 1998. Growth hormone regulation of SIRP and SHP-2 tyrosyl phosphorylation and association. J Biol Chem 273:7112–7117.PubMedCrossRefGoogle Scholar
  55. Sumimoto, H., Imabayashi, F., Iwata, T. and Kawakami, Y. 2006. The BRAF-MAPK signaling pathway is essential for cancer-immune evasion in human melanoma cells. J Exp Med. 203:1651–1656.PubMedCrossRefGoogle Scholar
  56. Takeda, K., Clausen, B. E., Kaisho, T., Tsujimura, T., Terada, N., Forster, I. and Akira, S. 1999. Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. Immunity 10:39–49.PubMedCrossRefGoogle Scholar
  57. Tsukada, J., Ozaki, A., Hanada, T., Chinen, T., Abe, R., Yoshimura, A. and Kubo, M. 2005. The role of suppressor of cytokine signaling 1 as a negative regulator for aberrant expansion of CD8alpha+ dendritic cell subset. Int Immunol 17:1167–1178.PubMedCrossRefGoogle Scholar
  58. Turkson, J. and Jove, R. 2000. STAT proteins: novel molecular targets for cancer drug discovery. Oncogene 19:6613–6626.PubMedCrossRefGoogle Scholar
  59. Turkson, J., Zhang, S., Palmer, J., Kay, H., Stanko, J., Mora, L. B., Sebti, S., Yu, H. and Jove, R. 2004. Inhibition of constitutive signal transducer and activator of transcription 3 activation by novel platinum complexes with potent antitumor activity. Mol Cancer Ther 3:1533–1542.PubMedGoogle Scholar
  60. Wang, R., Cherukuri, P. and Luo, J. 2005. Activation of Stat3 sequence-specific DNA binding and transcription by p300/CREB-binding protein-mediated acetylation. J Biol Chem 280:11528–11534.PubMedCrossRefGoogle Scholar
  61. Wang, T., Niu, G., Kortylewski, M., Burdelya, L., Shain, K., Zhang, S., Bhattacharya, R., Gabrilovich, D., Heller, R., Coppola, D., Dalton, W., Jove, R., Pardoll, D. and Yu, H. 2004. Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med 10:48–54.PubMedCrossRefGoogle Scholar
  62. Williams, J. G. 1999. Serpentine receptors and STAT activation: more than one way to twin a STAT. Trends Biochem Sci 24:333–334.PubMedCrossRefGoogle Scholar
  63. Yuan, Z. L., Guan, Y. J., Chatterjee, D. and Chin, Y. E. 2005. Stat3 dimerization regulated by reversible acetylation of a single lysine residue. Science 307:269–273.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.H. Lee Moffitt Cancer CenterUniversity of South FloridaTampaUSA

Personalised recommendations