Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Tumour immunology

Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment

Key Points

  • Many oncogenic signalling pathways converge on signal transducer and activator of transcription 3 (STAT3). As a result, STAT3 is constitutively activated in a range of cancers.

  • STAT3 is a broad transcriptional regulator, and constitutively active STAT3 leads to a gene-expression pattern that promotes tumour-cell survival and proliferation, tumour angiogenesis and metastasis.

  • STAT3 provides the first direct link between oncogenesis and immune evasion. STAT3 activity inhibits the expression of T helper 1 (TH1)-type immunostimulating molecules while promoting the expression of immunosuppressive factors.

  • STAT3 activity propagates from tumour cells to immune cells in the tumour microenvironment, thereby mediating immune evasion by blocking both the production and sensing of inflammatory signals by various components of the immune system.

  • The propagation of STAT3 activity from tumour cells to diverse immune cells, and from one immune cell type to another, and back to tumour cells, is accomplished by STAT3-regulated factors, such as interleukin-10 and vascular endothelial growth factor, that are also STAT3 activators.

  • Targeting STAT3 in either tumour cells or immune cells stimulates both innate and adaptive immune responses against the tumour.

  • Combining STAT3 targeting with other promising immunotherapeutic approach(es) is anticipated to generate optimal anti-tumour immune responses.

Abstract

Immune cells in the tumour microenvironment not only fail to mount an effective anti-tumour immune response, but also interact intimately with the transformed cells to promote oncogenesis actively. Signal transducer and activator of transcription 3 (STAT3), which is a point of convergence for numerous oncogenic signalling pathways, is constitutively activated both in tumour cells and in immune cells in the tumour microenvironment. Constitutively activated STAT3 inhibits the expression of mediators necessary for immune activation against tumour cells. Furthermore, STAT3 activity promotes the production of immunosuppressive factors that activate STAT3 in diverse immune-cell subsets, altering gene-expression programmes and, thereby, restraining anti-tumour immune responses. As such, STAT3 propagates several levels of crosstalk between tumour cells and their immunological microenvironment, leading to tumour-induced immunosuppression. Consequently, STAT3 has emerged as a promising target for cancer immunotherapy.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Constitutive activation of STAT3 by receptor and non-receptor tyrosine kinases.
Figure 2: STAT3 signalling allows crosstalk between tumour cells and dendritic cells, forming an immunosuppressive network.
Figure 3: STAT3 signalling facilitates communication between tumour cells and diverse immune-cell subsets, including tumour-associated regulatory T cells.
Figure 4: Targeting STAT3 for cancer immunotherapy.

References

  1. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).

    CAS  PubMed  Article  Google Scholar 

  2. Bishop, J. M. Cancer: what should be done? Science 278, 995 (1997).

    CAS  PubMed  Article  Google Scholar 

  3. Vogelstein, B. & Kinzler, K. W. The multistep nature of cancer. Trends Genet. 9, 138–141 (1993).

    CAS  PubMed  Article  Google Scholar 

  4. Dunn, G. P., Bruce, A. T., Ikeda, H., Old, L. J. & Schreiber, R. D. Cancer immunoediting: from immunosurveillance to tumor escape. Nature Immunol. 3, 991–998 (2002). This is an insightful review on the mechanisms of immune surveillance and immune editing of tumours.

    CAS  Article  Google Scholar 

  5. Pardoll, D. Does the immune system see tumors as foreign or self? Annu. Rev. Immunol. 21, 807–839 (2003).

    CAS  PubMed  Article  Google Scholar 

  6. Blattman, J. N. & Greenberg, P. D. Cancer immunotherapy: a treatment for the masses. Science 305, 200–205 (2004).

    CAS  PubMed  Article  Google Scholar 

  7. Gabrilovich, D. Mechanisms and functional significance of tumour-induced dendritic-cell defects. Nature Rev. Immunol. 4, 941–952 (2004).

    CAS  Article  Google Scholar 

  8. Zou, W. Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nature Rev. Cancer 5, 263–274 (2005).

    CAS  Article  Google Scholar 

  9. Bissell, M. J. & Radisky, D. Putting tumours in context. Nature Rev. Cancer 1, 46–54 (2001).

    CAS  Article  Google Scholar 

  10. Pollard, J. W. Tumour-educated macrophages promote tumour progression and metastasis. Nature Rev. Cancer 4, 71–78 (2004).

    CAS  Article  Google Scholar 

  11. Yu, C. L. et al. Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein. Science 269, 81–83 (1995). This study provides the first evidence that STAT3 has a role in oncogenesis in that STAT3 is constitutively activated by SRC oncoprotein.

    CAS  PubMed  Article  Google Scholar 

  12. Bromberg, J. & Darnell, J. E. The role of STATs in transcriptional control and their impact on cellular function. Oncogene 19, 2468–2473 (2000).

    CAS  PubMed  Article  Google Scholar 

  13. Yu, H. & Jove, R. The STATs of cancer — new molecular targets come of age. Nature Rev. Cancer 4, 97–105 (2004). A comprehensive review on the role of STAT3 in cancer progression and on STAT3 as a target for cancer therapy.

    CAS  Article  Google Scholar 

  14. Takeda, K. et al. Enhanced TH1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. Immunity 10, 39–49 (1999).

    CAS  PubMed  Article  Google Scholar 

  15. Welte, T. et al. STAT3 deletion during hematopoiesis causes Crohn's disease-like pathogenesis and lethality: a critical role of STAT3 in innate immunity. Proc. Natl Acad. Sci. USA 100, 1879–1884 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  16. Wang, T. et al. Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nature Med. 10, 48–54 (2004). This study provided the first evidence at the molecular level that oncogenesis, for which STAT3 is crucial, coordinates tumour immune evasion. STAT3 activity in tumour cells not only inhibits the expression of T H 1-type immune-stimulating molecules, it also promotes the expression of immunosuppressive factors, leading to the inhibition of DC maturation.

    PubMed  Article  CAS  Google Scholar 

  17. Kortylewski, M. et al. Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nature Med. 11, 1314–1321 (2005). This study shows that STAT3 is constitutively activated in diverse immune-cell subsets in the tumour microenvironment. STAT3 signalling allows tumour cells and local immune cells to resonate with one another, leading to immunosuppression.

    CAS  PubMed  Article  Google Scholar 

  18. Nabarro, S. et al. Coordinated oncogenic transformation and inhibition of host immune responses by the PAX3–FKHR fusion oncoprotein. J. Exp. Med. 202, 1399–1410 (2005). This paper shows that activation of STAT3 by an oncoprotein inhibits the host immune response in mouse models.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. Sumimoto, H., Imabayashi, F., Iwata, T. & Kawakami, Y. The BRAF–MAPK signaling pathway is essential for cancer-immune evasion in human melanoma cells. J. Exp. Med. 203, 1651–1656 (2006). Results from this paper show that both STAT3 activation and the BRAF–MAPK signalling pathway can promote the expression of immunosuppressive factors such as IL-6, IL-10 and VEGF in human melanoma cells. Blocking either of these oncogenic signalling pathways in DCs decreases tumour-factor-induced inhibition of IL-12 expression.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. Darnell, J. E., Kerr, I. M. & Stark, G. R. Jak–STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264, 1415–1421 (1994).

    CAS  PubMed  Article  Google Scholar 

  21. Taga, T. & Kishimoto, T. Gp130 and the interleukin-6 family of cytokines. Annu. Rev. Immunol. 15, 797–819 (1997).

    CAS  PubMed  Article  Google Scholar 

  22. Heinrich, P. C., Behrmann, I., Muller-Newen, G., Schaper, F. & Graeve, L. Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem. J. 334, 297–314 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. Darnell, J. E. Studies of IFN-induced transcriptional activation uncover the Jak–Stat pathway. J. Interferon Cytokine Res. 18, 549–554 (1998).

    CAS  PubMed  Article  Google Scholar 

  24. Stark, G. R., Kerr, I. M., Williams, B. R., Silverman, R. H. & Schreiber, R. D. How cells respond to interferons. Annu. Rev. Biochem. 67, 227–264 (1998).

    CAS  PubMed  Article  Google Scholar 

  25. Heinrich, P. C. et al. Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem. J. 374, 1–20 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. Wang, R., Cherukuri, P. & Luo, J. Activation of Stat3 sequence-specific DNA binding and transcription by p300/CREB-binding protein-mediated acetylation. J. Biol. Chem. 280, 11528–11534 (2005).

    CAS  PubMed  Article  Google Scholar 

  27. Yuan, Z. L., Guan, Y. J., Chatterjee, D. & Chin, Y. E. Stat3 dimerization regulated by reversible acetylation of a single lysine residue. Science 307, 269–273 (2005).

    CAS  PubMed  Article  Google Scholar 

  28. Silvennoinen, O., Schindler, C., Schlessinger, J. & Levy, D. E. Ras-independent growth factor signaling by transcription factor tyrosine phosphorylation. Science 261, 1736–1739 (1993).

    CAS  PubMed  Article  Google Scholar 

  29. Zhong, Z., Wen, Z. & Darnell, J. E. Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science 264, 95–98 (1994).

    CAS  PubMed  Article  Google Scholar 

  30. Ruff-Jamison, S. et al. Epidermal growth factor and lipopolysaccharide activate Stat3 transcription factor in mouse liver. J. Biol. Chem. 269, 21933–21935 (1994).

    CAS  PubMed  Article  Google Scholar 

  31. Alexander, W. S. Suppressors of cytokine signalling (SOCS) in the immune system. Nature Rev. Immunol. 2, 410–416 (2002).

    CAS  Article  Google Scholar 

  32. Kubo, M., Hanada, T. & Yoshimura, A. Suppressors of cytokine signaling and immunity. Nature Immunol. 4, 1169–1176 (2003).

    CAS  Article  Google Scholar 

  33. Shuai, K. & Liu, B. Regulation of gene-activation pathways by PIAS proteins in the immune system. Nature Rev. Immunol. 5, 593–605 (2005).

    CAS  Article  Google Scholar 

  34. Turkson, J. et al. Stat3 activation by Src induces specific gene regulation and is required for cell transformation. Mol. Cell. Biol. 18, 2545–2552 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. Bromberg, J. F., Horvath, C. M., Besser, D., Lathem, W. W. & Darnell, J. E. Stat3 activation is required for cellular transformation by v-src. Mol. Cell. Biol. 18, 2553–2558 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. Bromberg, J. F. et al. Stat3 as an oncogene. Cell 98, 295–303 (1999). Using a constitutively active mutant form of STAT3, this study formally establishes that STAT3 is an oncoprotein.

    CAS  PubMed  Article  Google Scholar 

  37. Catlett-Falcone, R. et al. Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity 10, 105–115 (1999).

    CAS  Article  PubMed  Google Scholar 

  38. Grandis, J. R. et al. Requirement of Stat3 but not Stat1 activation for epidermal growth factor receptor-mediated cell growth in vitro. J. Clin. Invest. 102, 1385–1392 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. Coffer, P. J., Koenderman, L. & de Groot, R. P. The role of STATs in myeloid differentiation and leukemia. Oncogene 19, 2511–2522 (2000).

    CAS  Article  PubMed  Google Scholar 

  40. Lin, T. S., Mahajan, S. & Frank, D. A. STAT signaling in the pathogenesis and treatment of leukemias. Oncogene 19, 2496–2504 (2000).

    CAS  Article  PubMed  Google Scholar 

  41. Kortylewski, M., Jove, R. & Yu, H. Targeting STAT3 affects melanoma on multiple fronts. Cancer Metastasis Rev. 24, 315–327 (2005).

    CAS  Article  PubMed  Google Scholar 

  42. Niu, G. et al. Gene therapy with dominant-negative Stat3 suppresses growth of the murine melanoma B16 tumor in vivo. Cancer Res. 59, 5059–5063 (1999).

    CAS  PubMed  Google Scholar 

  43. Niu, G. et al. Overexpression of a dominant-negative signal transducer and activator of transcription 3 variant in tumor cells leads to production of soluble factors that induce apoptosis and cell cycle arrest. Cancer Res. 61, 3276–3280 (2001).

    CAS  PubMed  Google Scholar 

  44. Niu, G. et al. Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 21, 2000–2008 (2002).

    CAS  Article  PubMed  Google Scholar 

  45. Wei, D. et al. Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis. Oncogene 22, 319–329 (2003).

    CAS  Article  PubMed  Google Scholar 

  46. Wei, L. H. et al. Interleukin-6 promotes cervical tumor growth by VEGF-dependent angiogenesis via a STAT3 pathway. Oncogene 22, 1517–1527 (2003).

    CAS  Article  PubMed  Google Scholar 

  47. Xu, Q. et al. Targeting Stat3 blocks both HIF-1 and VEGF expression induced by multiple oncogenic growth signaling pathways. Oncogene 24, 5552–5560 (2005).

    CAS  Article  PubMed  Google Scholar 

  48. Wojcik, E. J. et al. A novel activating function of c-Src and Stat3 on HGF transcription in mammary carcinoma cells. Oncogene 25, 2773–2784 (2006).

    CAS  PubMed  Article  Google Scholar 

  49. Xie, T. X. et al. Stat3 activation regulates the expression of matrix metalloproteinase-2 and tumor invasion and metastasis. Oncogene 23, 3550–3560 (2004).

    CAS  Article  PubMed  Google Scholar 

  50. Dechow, T. N. et al. Requirement of matrix metalloproteinase-9 for the transformation of human mammary epithelial cells by Stat3-C. Proc. Natl Acad. Sci. USA 101, 10602–10607 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. Burdelya, L. et al. Stat3 activity in melanoma cells affects migration of immune effector cells and nitric oxide-mediated antitumor effects. J. Immunol. 174, 3925–3931 (2005).

    CAS  PubMed  Article  Google Scholar 

  52. Vicari, A. P., Caux, C. & Trinchieri, G. Tumour escape from immune surveillance through dendritic cell inactivation. Semin. Cancer Biol. 12, 33–42 (2002).

    CAS  PubMed  Article  Google Scholar 

  53. Steinman, R. M., Hawiger, D. & Nussenzweig, M. C. Tolerogenic dendritic cells. Annu. Rev. Immunol. 21, 685–711 (2003).

    CAS  PubMed  Article  Google Scholar 

  54. Nefedova, Y. et al. Hyperactivation of STAT3 is involved in abnormal differentiation of dendritic cells in cancer. J. Immunol. 172, 464–474 (2004).

    CAS  PubMed  Article  Google Scholar 

  55. Park, S. J. et al. IL-6 regulates in vivo dendritic cell differentiation through STAT3 activation. J. Immunol. 173, 3844–3854 (2004).

    CAS  PubMed  Article  Google Scholar 

  56. Kawakami, Y. et al. Regulation of dendritic cell maturation and function by Bruton's tyrosine kinase via IL-10 and Stat3. Proc. Natl Acad. Sci. USA 103, 153–158 (2006).

    CAS  PubMed  Article  Google Scholar 

  57. Cheng, F. et al. A critical role for Stat3 signaling in immune tolerance. Immunity 19, 425–436 (2003).

    CAS  PubMed  Article  Google Scholar 

  58. Sun, Z., Yao, Z., Liu, S., Tang, H. & Yan, X. An oligonucleotide decoy for Stat3 activates the immune response of macrophages to breast cancer. Immunobiology 211, 199–209 (2006).

    CAS  Article  PubMed  Google Scholar 

  59. Yu, P. et al. Intratumor depletion of CD4+ cells unmasks tumor immunogenicity leading to the rejection of late-stage tumors. J. Exp. Med. 201, 779–791 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. Nishikawa, H. et al. IFN-γ controls the generation/activation of CD4+ CD25+ regulatory T cells in antitumor immune response. J. Immunol. 175, 4433–4440 (2005).

    CAS  Article  PubMed  Google Scholar 

  61. Larmonier, N. et al. Tumor-derived CD4+CD25+ regulatory T cell suppression of dendritic cell function involves TGF-β and IL-10. Cancer Immunol. Immunother. 56, 48–59 (2007).

    CAS  Article  PubMed  Google Scholar 

  62. Liyanage, U. K. et al. Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J. Immunol. 169, 2756–2761 (2002).

    CAS  Article  PubMed  Google Scholar 

  63. Woo, E. Y. et al. Regulatory CD4+CD25+ T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer. Cancer Res. 61, 4766–4772 (2001).

    CAS  PubMed  Google Scholar 

  64. Zou, W. Regulatory T cells, tumour immunity and immunotherapy. Nature Rev. Immunol. 6, 295–307 (2006).

    CAS  Article  Google Scholar 

  65. Curiel, T. J. et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nature Med. 10, 942–949 (2004).

    CAS  Article  PubMed  Google Scholar 

  66. Wei, S. et al. Plasmacytoid dendritic cells induce CD8+ regulatory T cells in human ovarian carcinoma. Cancer Res. 65, 5020–5026 (2005).

    CAS  Article  PubMed  Google Scholar 

  67. Sakaguchi, S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nature Immunol. 6, 345–352 (2005).

    CAS  Article  Google Scholar 

  68. Shevach, E. M. CD4+ CD25+ suppressor T cells: more questions than answers. Nature Rev. Immunol. 2, 389–400 (2002).

    CAS  Article  Google Scholar 

  69. Chen, W. et al. Conversion of peripheral CD4+CD25 naive T cells to CD4+CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3. J. Exp. Med. 198, 1875–1886 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. Fantini, M. C. et al. Cutting edge: TGF-β induces a regulatory phenotype in CD4+CD25 T cells through Foxp3 induction and down-regulation of Smad7. J. Immunol. 172, 5149–5153 (2004).

    CAS  PubMed  Article  Google Scholar 

  71. Kinjyo, I. et al. Loss of SOCS3 in T helper cells resulted in reduced immune responses and hyperproduction of interleukin 10 and transforming growth factor-β1. J. Exp. Med. 203, 1021–1031 (2006). This study shows that increased STAT3 signalling, as a result of Socs3 ablation, is crucial for the expression of IL-10 and TGF-β by T H cells, indicating a crucial role for STAT3 in T Reg cells.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. Kasprzycka, M., Marzec, M., Liu, X., Zhang, Q. & Wasik, M. A. Nucleophosmin/anaplastic lymphoma kinase (NPM/ALK) oncoprotein induces the T regulatory cell phenotype by activating STAT3. Proc. Natl Acad. Sci. USA 103, 9964–9969 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  73. Doganci, A. et al. The IL-6Rα chain controls lung CD4+CD25+ TR eg development and function during allergic airway inflammation in vivo. J. Clin. Invest. 115, 313–325 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. Zorn, E. et al. IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo. Blood 108, 1571–1579 (2006). This paper shows that IL-2-induced FOXP3 expression in human T Reg cells is mediated by STAT3 and STAT5.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. Antov, A., Yang, L., Vig, M., Baltimore, D. & Van Parijs, L. Essential role for STAT5 signaling in CD25+CD4+ regulatory T cell homeostasis and the maintenance of self-tolerance. J. Immunol. 171, 3435–3441 (2003).

    CAS  PubMed  Article  Google Scholar 

  76. Snow, J. W. et al. Loss of tolerance and autoimmunity affecting multiple organs in STAT5A/5B-deficient mice. J. Immunol. 171, 5042–5050 (2003).

    CAS  PubMed  Article  Google Scholar 

  77. Chan, S. M., Ermann, J., Su, L., Fathman, C. G. & Utz, P. J. Protein microarrays for multiplex analysis of signal transduction pathways. Nature Med. 10, 1390–1396 (2004).

    CAS  Article  PubMed  Google Scholar 

  78. Anderson, P. O. et al. IL-2 overcomes the unresponsiveness but fails to reverse the regulatory function of antigen-induced T regulatory cells. J. Immunol. 174, 310–319 (2005).

    CAS  Article  PubMed  Google Scholar 

  79. Dercamp, C., Chemin, K., Caux, C., Trinchieri, G. & Vicari, A. P. Distinct and overlapping roles of interleukin-10 and CD25+ regulatory T cells in the inhibition of antitumor CD8 T-cell responses. Cancer Res. 65, 8479–8486 (2005).

    CAS  Article  PubMed  Google Scholar 

  80. Langowski, J. L. et al. IL-23 promotes tumour incidence and growth. Nature 442, 461–465 (2006).

    CAS  PubMed  Article  Google Scholar 

  81. Hoentjen, F., Sartor, R. B., Ozaki, M. & Jobin, C. STAT3 regulates NF-κB recruitment to the IL-12p40 promoter in dendritic cells. Blood 105, 689–696 (2005).

    CAS  PubMed  Article  Google Scholar 

  82. Chen, Z. et al. Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells. Proc. Natl Acad. Sci. USA 103, 8137–8142 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  83. Karin, M. & Greten, F. R. NF-κB: linking inflammation and immunity to cancer development and progression. Nature Rev. Immunol. 5, 749–759 (2005).

    CAS  Article  Google Scholar 

  84. Dalwadi, H. et al. Cyclooxygenase-2-dependent activation of signal transducer and activator of transcription 3 by interleukin-6 in non-small cell lung cancer. Clin. Cancer Res. 11, 7674–7682 (2005).

    CAS  Article  PubMed  Google Scholar 

  85. Shankaran, V. et al. IFNγ and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410, 1107–1111 (2001).

    CAS  PubMed  Article  Google Scholar 

  86. Alonzi, T. et al. Induced somatic inactivation of STAT3 in mice triggers the development of a fulminant form of enterocolitis. Cytokine 26, 45–56 (2004).

    CAS  Article  PubMed  Google Scholar 

  87. Turkson, J. et al. Phosphotyrosyl peptides block Stat3-mediated DNA binding activity, gene regulation, and cell transformation. J. Biol. Chem. 276, 45443–45455 (2001).

    CAS  Article  PubMed  Google Scholar 

  88. Turkson, J. et al. A novel platinum compound inhibits constitutive Stat3 signaling and induces cell cycle arrest and apoptosis of malignant cells. J. Biol. Chem. 280, 32979–32988 (2005).

    CAS  Article  PubMed  Google Scholar 

  89. Turkson, J. et al. 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 (2004).

    CAS  PubMed  Google Scholar 

  90. van Elsas, A., Hurwitz, A. A. & Allison, J. P. Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation. J. Exp. Med. 190, 355–366 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  91. Riley, J. L. & June, C. H. The CD28 family: a T-cell rheostat for therapeutic control of T-cell activation. Blood 105, 13–21 (2005).

    CAS  PubMed  Article  Google Scholar 

  92. Shen, L., Evel-Kabler, K., Strube, R. & Chen, S. Y. Silencing of SOCS1 enhances antigen presentation by dendritic cells and antigen-specific anti-tumor immunity. Nature Biotechnol. 22, 1546–1553 (2004).

    CAS  Article  Google Scholar 

  93. Kryczek, I. et al. B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma. J. Exp. Med. 203, 871–881 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. Mellor, A. L. & Munn, D. H. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nature Rev. Immunol. 4, 762–774 (2004).

    CAS  Article  Google Scholar 

  95. Rosenberg, S. A., Yang, J. C. & Restifo, N. P. Cancer immunotherapy: moving beyond current vaccines. Nature Med. 10, 909–915 (2004).

    CAS  PubMed  Article  Google Scholar 

  96. Pardoll, D. M. Spinning molecular immunology into successful immunotherapy. Nature Rev. Immunol. 2, 227–238 (2002).

    CAS  Article  Google Scholar 

  97. Steinman, R. M. & Mellman, I. Immunotherapy: bewitched, bothered, and bewildered no more. Science 305, 197–200 (2004).

    CAS  PubMed  Article  Google Scholar 

  98. Vicari, A. P. et al. Reversal of tumor-induced dendritic cell paralysis by CpG immunostimulatory oligonucleotide and anti-interleukin 10 receptor antibody. J. Exp. Med. 196, 541–549 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. Nefedova, Y. et al. 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 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  100. Kitamura, H. et al. IL-6–STAT3 controls intracellular MHC class II αβ dimer level through cathepsin S activity in dendritic cells. Immunity 23, 491–502 (2005).

    CAS  PubMed  Article  Google Scholar 

  101. Kammertoens, T., Schuler, T. & Blankenstein, T. Immunotherapy: target the stroma to hit the tumor. Trends Mol. Med. 11, 225–231 (2005).

    CAS  PubMed  Article  Google Scholar 

  102. Wang, S. et al. Tumor evasion of the immune system: inhibiting p38 MAPK signaling restores the function of dendritic cells in multiple myeloma. Blood 107, 2432–2439 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  103. Dauer, D. J. et al. Stat3 regulates genes common to both wound healing and cancer. Oncogene 24, 3397–3408 (2005).

    CAS  PubMed  Article  Google Scholar 

  104. Sano, S. et al. Keratinocyte-specific ablation of Stat3 exhibits impaired skin remodeling, but does not affect skin morphogenesis. EMBO J. 18, 4657–4668 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  105. Chiarle, R. et al. Stat3 is required for ALK-mediated lymphomagenesis and provides a possible therapeutic target. Nature Med. 11, 623–629 (2005).

    CAS  PubMed  Article  Google Scholar 

  106. Okada, S. et al. Conditional ablation of Stat3 or Socs3 discloses a dual role for reactive astrocytes after spinal cord injury. Nature Med. 12, 829–834 (2006).

    CAS  PubMed  Article  Google Scholar 

  107. Odajima, J. et al. Full oncogenic activities of v-Src are mediated by multiple signaling pathways. Ras as an essential mediator for cell survival. J. Biol. Chem. 275, 24096–24105 (2000).

    CAS  PubMed  Article  Google Scholar 

  108. Ning, Z. Q., Li, J., McGuinness, M. & Arceci, R. J. STAT3 activation is required for Asp816 mutant c-Kit induced tumorigenicity. Oncogene 20, 4528–4536 (2001).

    CAS  PubMed  Article  Google Scholar 

  109. Bowman, T. et al. Stat3-mediated Myc expression is required for Src transformation and PDGF-induced mitogenesis. Proc. Natl Acad. Sci. USA 98, 7319–7324 (2001).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  110. Sinibaldi, D. et al. Induction of p21WAF1/CIP1 and cyclin D1 expression by the Src oncoprotein in mouse fibroblasts: role of activated STAT3 signaling. Oncogene 19, 5419–5427 (2000).

    CAS  PubMed  Article  Google Scholar 

  111. Karni, R., Jove, R. & Levitzki, A. Inhibition of pp60c-Src reduces Bcl-XL expression and reverses the transformed phenotype of cells overexpressing EGF and HER-2 receptors. Oncogene 18, 4654–4662 (1999).

    CAS  PubMed  Article  Google Scholar 

  112. Epling-Burnette, P. K. et al. Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-1 expression. J. Clin. Invest. 107, 351–362 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  113. Niu, G. et al. Roles of activated Src and Stat3 signaling in melanoma tumor cell growth. Oncogene 21, 7001–7010 (2002).

    CAS  PubMed  Article  Google Scholar 

  114. Aoki, Y., Feldman, G. M. & Tosato, G. Inhibition of STAT3 signaling induces apoptosis and decreases survivin expression in primary effusion lymphoma. Blood 101, 1535–1542 (2003).

    CAS  PubMed  Article  Google Scholar 

  115. Amin, H. M. et al. Selective inhibition of STAT3 induces apoptosis and G1 cell cycle arrest in ALK-positive anaplastic large cell lymphoma. Oncogene 23, 5426–5434 (2004).

    CAS  Article  PubMed  Google Scholar 

  116. Gritsko, T. et al. Persistent activation of stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells. Clin. Cancer Res. 12, 11–19 (2006).

    CAS  PubMed  Article  Google Scholar 

  117. Niu, G. et al. Role of Stat3 in regulating p53 expression and function. Mol. Cell. Biol. 25, 7432–7440 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  118. Hung, W. & Elliott, B. Co-operative effect of c-Src tyrosine kinase and Stat3 in activation of hepatocyte growth factor expression in mammary carcinoma cells. J. Biol. Chem. 276, 12395–12403 (2001).

    CAS  PubMed  Article  Google Scholar 

  119. Xie, T. X. et al. Activation of stat3 in human melanoma promotes brain metastasis. Cancer Res. 66, 3188–3196 (2006).

    CAS  PubMed  Article  Google Scholar 

  120. Jung, J. E. et al. STAT3 is a potential modulator of HIF-1-mediated VEGF expression in human renal carcinoma cells. FASEB J. 19, 1296–1298 (2005).

    CAS  PubMed  Article  Google Scholar 

  121. Herbeuval, J. P., Lelievre, E., Lambert, C., Dy, M. & Genin, C. Recruitment of STAT3 for production of IL-10 by colon carcinoma cells induced by macrophage-derived IL-6. J. Immunol. 172, 4630–4636 (2004).

    CAS  PubMed  Article  Google Scholar 

Download references

Acknowledgements

We would like to thank members of our laboratory, especially G.-L. Niu, M. Kujawski, T.-H. Wang and L. Burdelya, for their contributions to the work summarized here. We would also like to acknowledge the pioneering work of R. Jove in linking STAT3 with cancer that inspired the initial gene-therapy experiment. H.Y. was supported by US National Institutes of Health (NIH) grants and by the Dr Tsai-fan Yu Cancer Research Endowment. D.P. was supported by NIH grants and gifts from the Topercer family, D. Needle, J. Goldsmith, the Seraph Foundation and the Janney Fund.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hua Yu.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Laboratory of Hua Yu

Glossary

Danger signals

A danger signal is normally defined as the pathogen-associated molecular pattern that is recognized by host receptors. Danger signals often trigger the production of cytokines, chemokines and other physiological mediators, such as nitric oxide, leading to immune responses against the pathogen. In the context of this Review, 'danger signals' refer to the similar cytokines, chemokines and other T helper 1-type immunostimulating molecules that are produced by transformed cells on STAT3 inhibition.

Tolerogenic dendritic cells

Dendritic cells that can attenuate T-cell-mediated immune responses by anergizing or changing the effector function of antigen-specific T cells.

Mx1–Cre–loxP system

The Mx1–Cre–loxP system allows specific gene ablation, mostly in the haematopoietic cell lineages of adult mice. Injection of polyinosinic–polycytidylic-acid oligonucleotides stimulates the production of type-I interferons, which induce Cre recombinase expression through the interferon-sensitive Mx1 promoter, resulting in the ablation of target gene alleles flanked by loxP sites.

T-cell anergy

A state of T-cell unresponsiveness to stimulation with antigen. It can be induced by stimulation with a large amount of specific antigen in the absence of the engagement of co-stimulatory molecules.

Regulatory T (TReg) cells

A rare population of CD4+ T cells that naturally express high levels of CD25 (the interleukin-2 receptor α-chain) and the transcription factor forkhead box P3 (FOXP3), and that have suppressive regulatory activity towards effector T cells and other immune cells. Absence or dysfunction of TReg cells is associated with severe autoimmunity. In tumours, TReg cells are induced and proliferate, thereby suppressing anti-tumour immunity.

Plasmacytoid dendritic cells

A subset of dendritic cells (DCs) that are described as plasmacytoid because of their microscopic appearance that resembles plasmablasts. In humans, these DCs can be derived from lineage-negative stem cells in peripheral blood and are the main producers of type-I interferon (IFN) in response to virus infections. Recent studies have identified a subset of type-I IFN-producing DCs in mice, which are characterized by expression of B220 and Ly6C.

Nucleophosmin/anaplastic lymphoma kinase (NPM/ALK) oncoprotein

An oncogenic fusion tyrosine kinase that is associated with a specific type of non-Hodgkin's lymphoma. The translocation between chromosomes 5 and 2 results in fusion of the amino-terminal part of the ubiquitous nucleolar protein NPM to the cytoplasmic fragment of the receptor tyrosine kinase ALK, creating a hybrid tyrosine kinase with constitutive activity.

Immune-mediated colitis

An inflammatory disease of the colon most commonly classified as ulcerative colitis or Crohn's disease. Various hereditary and induced mouse models of human colitis have been developed.

RNA interference

(RNAi). Double-stranded RNAs (dsRNAs) with sequences that precisely match a given gene are able to 'knock down' the expression of that gene by directing RNA-degrading enzymes to destroy the encoded mRNA transcript. The two most common forms of dsRNAs used for gene silencing are short — usually 21-bp long — small interfering RNAs (siRNAs) or the plasmid-delivered short hairpin RNAs (shRNAs).

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Yu, H., Kortylewski, M. & Pardoll, D. Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol 7, 41–51 (2007). https://doi.org/10.1038/nri1995

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri1995

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing