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.

Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity

Abstract

The immune system can act as an extrinsic suppressor of tumors. Therefore, tumor progression depends in part on mechanisms that downmodulate intrinsic immune surveillance. Identifying these inhibitory pathways may provide promising targets to enhance antitumor immunity. Here, we show that Stat3 is constitutively activated in diverse tumor-infiltrating immune cells, and ablating Stat3 in hematopoietic cells triggers an intrinsic immune-surveillance system that inhibits tumor growth and metastasis. We observed a markedly enhanced function of dendritic cells, T cells, natural killer (NK) cells and neutrophils in tumor-bearing mice with Stat3−/− hematopoietic cells, and showed that tumor regression requires immune cells. Targeting Stat3 with a small-molecule drug induces T cell– and NK cell–dependent growth inhibition of established tumors otherwise resistant to direct killing by the inhibitor. Our findings show that Stat3 signaling restrains natural tumor immune surveillance and that inhibiting hematopoietic Stat3 in tumor-bearing hosts elicits multicomponent therapeutic antitumor immunity.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Inducing Stat3 ablation in hematopoietic cells of adult mice.
Figure 2: Effects of Stat3 ablation on DCs.
Figure 3: Role of Stat3 signaling in neutrophils and NK cells.
Figure 4: Characterization of T cells from tumor bearing mice with Stat3−/− hematopoietic system.
Figure 5: Ablating Stat3 in hematopoietic cells induces antitumor effects.
Figure 6: Targeting Stat3 with a small-molecule inhibitor activates antitumor immunity.

References

  1. 1

    Dunn, G.P., Bruce, A.T., Ikeda, H., Old, L.J. & Schreiber, R.D. Cancer immunoediting: from immunosurveillance to tumor escape. Nat. Immunol. 3, 991–998 (2002).

    CAS  Article  Google Scholar 

  2. 2

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

    CAS  Article  Google Scholar 

  3. 3

    Hawiger, D. et al. Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo. J. Exp. Med. 194, 769–779 (2001).

    CAS  Article  Google Scholar 

  4. 4

    Sotomayor, E.M. et al. Cross-presentation of tumor antigens by bone marrow-derived antigen-presenting cells is the dominant mechanism in the induction of T-cell tolerance during B-cell lymphoma progression. Blood 98, 1070–1077 (2001).

    CAS  Article  Google Scholar 

  5. 5

    Spiotto, M.T. et al. Increasing tumor antigen expression overcomes “ignorance” to solid tumors via crosspresentation by bone marrow-derived stromal cells. Immunity 17, 737–747 (2002).

    CAS  Article  Google Scholar 

  6. 6

    Lanzavecchia, A. & Sallusto, F. Regulation of T cell immunity by dendritic cells. Cell 106, 263–266 (2001).

    CAS  Article  Google Scholar 

  7. 7

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

    CAS  Article  Google Scholar 

  8. 8

    Almand, B. et al. Clinical significance of defective dendritic cell differentiation in cancer. Clin. Cancer Res. 6, 1755–1766 (2000).

    CAS  PubMed  Google Scholar 

  9. 9

    Ratta, M. et al. Dendritic cells are functionally defective in multiple myeloma: the role of interleukin-6. Blood 100, 230–237 (2002).

    CAS  Article  Google Scholar 

  10. 10

    Melani, C., Chiodoni, C., Forni, G. & Colombo, M.P. Myeloid cell expansion elicited by the progression of spontaneous mammary carcinomas in c-erbB-2 transgenic BALB/c mice suppresses immune reactivity. Blood 102, 2138–2145 (2003).

    CAS  Article  Google Scholar 

  11. 11

    Wang, T. et al. Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat. Med. 10, 48–54 (2004).

    Article  Google Scholar 

  12. 12

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

    CAS  Article  Google Scholar 

  13. 13

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

    CAS  Article  Google Scholar 

  14. 14

    Laouar, Y., Welte, T., Fu, X.Y. & Flavell, R.A. STAT3 is required for Flt3L-dependent dendritic cell differentiation. Immunity 19, 903–912 (2003).

    CAS  Article  Google Scholar 

  15. 15

    Takeda, K. et al. Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. Proc. Natl. Acad. Sci. USA 94, 3801–3804 (1997).

    CAS  Article  Google Scholar 

  16. 16

    Kuhn, R., Schwenk, F., Aguet, M. & Rajewsky, K. Inducible gene targeting in mice. Science 269, 1427–1429 (1995).

    CAS  Article  Google Scholar 

  17. 17

    Lee, C.K. et al. STAT3 is a negative regulator of granulopoiesis but is not required for G-CSF-dependent differentiation. Immunity 17, 63–72 (2002).

    CAS  Article  Google Scholar 

  18. 18

    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  Article  Google Scholar 

  19. 19

    Coussens, L.M. & Werb, Z. Inflammation and cancer. Nature 420, 860–867 (2002).

    CAS  Article  Google Scholar 

  20. 20

    Guiducci, C., Vicari, A.P., Sangaletti, S., Trinchieri, G. & Colombo, M.P. Redirecting in vivo elicited tumor infiltrating macrophages and dendritic cells towards tumor rejection. Cancer Res. 65, 3437–3446 (2005).

    CAS  Article  Google Scholar 

  21. 21

    Mantovani, A., Sozzani, S., Locati, M., Allavena, P. & Sica, A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 23, 549–555 (2002).

    CAS  Article  Google Scholar 

  22. 22

    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  Article  Google Scholar 

  23. 23

    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  Article  Google Scholar 

  24. 24

    Colonna, M., Trinchieri, G. & Liu, Y.J. Plasmacytoid dendritic cells in immunity. Nat. Immunol. 5, 1219–1226 (2004).

    CAS  Article  Google Scholar 

  25. 25

    Degli-Esposti, M.A. & Smyth, M.J. Close encounters of different kinds: dendritic cells and NK cells take centre stage. Nat. Rev. Immunol. 5, 112–124 (2005).

    CAS  Article  Google Scholar 

  26. 26

    Diefenbach, A., Jamieson, A.M., Liu, S.D., Shastri, N. & Raulet, D.H. Ligands for the murine NKG2D receptor: expression by tumor cells and activation of NK cells and macrophages. Nat. Immunol. 1, 119–126 (2000).

    CAS  Article  Google Scholar 

  27. 27

    Dranoff, G. Cytokines in cancer pathogenesis and cancer therapy. Nat. Rev. Cancer 4, 11–22 (2004).

    CAS  Article  Google Scholar 

  28. 28

    Golumbek, P.T. et al. Treatment of established renal cancer by tumor cells engineered to secrete interleukin-4. Science 254, 713–716 (1991).

    CAS  Article  Google Scholar 

  29. 29

    Smyth, M.J. et al. Differential tumor surveillance by natural killer (NK) and NKT cells. J. Exp. Med. 191, 661–668 (2000).

    CAS  Article  Google Scholar 

  30. 30

    Halak, B.K., Maguire, H.C., Jr . & Lattime, E.C. Tumor-induced interleukin-10 inhibits type 1 immune responses directed at a tumor antigen as well as a non-tumor antigen present at the tumor site. Cancer Res. 59, 911–917 (1999).

    CAS  PubMed  Google Scholar 

  31. 31

    Ivanov, V.N. et al. Cooperation between STAT3 and c-jun suppresses Fas transcription. Mol. Cell 7, 517–528 (2001).

    CAS  Article  Google Scholar 

  32. 32

    Ho, W.Y., Blattman, J.N., Dossett, M.L., Yee, C. & Greenberg, P.D. Adoptive immunotherapy: engineering T cell responses as biologic weapons for tumor mass destruction. Cancer Cell 3, 431–437 (2003).

    CAS  Article  Google Scholar 

  33. 33

    Spiotto, M.T., Rowley, D.A. & Schreiber, H. Bystander elimination of antigen loss variants in established tumors. Nat. Med. 10, 294–298 (2004).

    CAS  Article  Google Scholar 

  34. 34

    Turk, M.J. et al. Concomitant tumor immunity to a poorly immunogenic melanoma is prevented by regulatory T cells. J. Exp. Med. 200, 771–782 (2004).

    CAS  Article  Google Scholar 

  35. 35

    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  Google Scholar 

  36. 36

    Turkson, J. et al. Inhibition of constitutive Stat3 activation by novel platinum complexes with potent anti-tumor activity. Mol. Cancer Ther. 3, 1533–1542 (2004).

    CAS  PubMed  Google Scholar 

  37. 37

    Shen, Y., Devgan, G., Darnell, J.E., Jr . & Bromberg, J.F. Constitutively activated Stat3 protects fibroblasts from serum withdrawal and UV-induced apoptosis and antagonizes the proapoptotic effects of activated Stat1. Proc. Natl. Acad. Sci. USA 98, 1543–1548 (2001).

    CAS  Article  Google Scholar 

  38. 38

    Costa-Pereira, A.P. et al. Mutational switch of an IL-6 response to an interferon-gamma-like response. Proc. Natl. Acad. Sci. USA 99, 8043–8047 (2002).

    CAS  Article  Google Scholar 

  39. 39

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

    CAS  Article  Google Scholar 

  40. 40

    Yu, H. & Jove, R. The STATs of cancer–new molecular targets come of age. Nat. Rev. Cancer 4, 97–105 (2004).

    CAS  Article  Google Scholar 

  41. 41

    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 

  42. 42

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

    CAS  Article  Google Scholar 

  43. 43

    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  Article  Google Scholar 

  44. 44

    Wang, J.W. et al. Influence of SHIP on the NK repertoire and allogeneic bone marrow transplantation. Science 295, 2094–2097 (2002).

    CAS  Article  Google Scholar 

  45. 45

    Furumoto, K. et al. Spleen-derived dendritic cells engineered to enhance interleukin-12 production elicit therapeutic antitumor immune responses. Int. J. Cancer 87, 665–672 (2000).

    CAS  Article  Google Scholar 

  46. 46

    Wei, S. et al. Control of lytic function by mitogen-activated protein kinase/extracellular regulatory kinase 2 (ERK2) in a human natural killer cell line: identification of perforin and granzyme B mobilization by functional ERK2. J. Exp. Med. 187, 1753–1765 (1998).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We would like to thank G. Gao for statistical analyses, C. Muro-Cacho for evaluating immunohistochemical data, K. Nguyen and T. Ghansah for sharing their expertise and L. Lutz for technical assistance. This work was supported by US National Institutes of Health grants (to H.Y.), and by the Dr. Tsai-fan Yu Cancer Research Endowment. Work in D.P.'s lab was supported by grants from the Commonwealth Foundation, Janey Fund, the Seraph Foundation, the Topecers and D. Needle. W.G.K. is the Newman Scholar of the Leukemia and Lymphoma Society. We would also like to thank S. Akira and K. Takeda for Stat3loxP mice, and the Pathology Core at the University of South Florida for technical assistance. We also acknowledge dedication of staff members at the animal facilities and flow cytometry cores at both Moffitt Cancer Center and Johns Hopkins Cancer Center.

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Drew Pardoll or Hua Yu.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

The inflammatory effects of poly(I:C) injections are rapid and transient. (PDF 173 kb)

Supplementary Fig. 2

Effects of Stat3 ablation on CD8+ and B220+ CD11c+ DCs. (PDF 208 kb)

Supplementary Fig. 3

IL-10 activates Stat3 in both NK cells and granulocytes. (PDF 182 kb)

Supplementary Fig. 4

FasL expression is increased in tumorinfiltrating neutrophils in Stat3−/− mice. (PDF 193 kb)

Supplementary Fig. 5

Stat3 inhibition and autoimmune responses in tumor-bearing mice. (PDF 195 kb)

Supplementary Fig. 6

CPA-7 inhibits Stat3 but not Stat1 or Stat5 activation in dendritic cells. (PDF 174 kb)

Supplementary Fig. 7

Targeting Stat3 inhibits tumor metastasis and prolongs survival of tumor-bearing hosts. (PDF 212 kb)

Supplementary Table 1

No major toxic effects of long-term Stat3 inhibition by a small-molecule drug. (PDF 26 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kortylewski, M., Kujawski, M., Wang, T. et al. Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat Med 11, 1314–1321 (2005). https://doi.org/10.1038/nm1325

Download citation

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