Skip to main content

Advertisement

SpringerLink
Log in

Effect of tumor-derived cytokines and growth factors on differentiation and immune suppressive features of myeloid cells in cancer

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

It is well established that cancers affect differentiation of dendritic cells and promote systemic expansion of immune suppressive immature myeloid cells. This phenomenon may represent a mechanism of tumor escape from immune attack and could have significant impact on tumor progression. In this review we discuss the role of different tumor-derived factors, which were implicated in abnormal myeloid cell differentiation. The role of reactive oxygen species as well as JAK/STAT signaling in mechanisms of the effects of tumor-derived factors on myeloid cells is also discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Kusmartsev, S., Li, Y., & Chen, S.-H. (2000). Gr-1+ myeloid cells derived from tumor-bearing mice inhibit primary T cell activation induced through CD3/CD28 costimulation. Journal of Immunology, 165, 779–785.

    CAS  Google Scholar 

  2. Melani, C., Chiodoni, C., Forni, G., & Colombo, M. P. (2003). 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.

    Article  CAS  PubMed  Google Scholar 

  3. Kusmartsev, S., Cheng, F., Yu, B., Nefedova, Y., Sotomayor, E., & Lush, R., et al. (2003). All-trans-retinoic acid eliminates immature myeloid cells from tumor-bearing mice and improves the effect of vaccination. Cancer Research, 63, 4441–4449.

    CAS  PubMed  Google Scholar 

  4. Salvadori, S., Martinelli, G., & Zier, K. (2000). Resection of solid tumors reverses T cell defects and restores protective immunity. Journal of Immunology, 164, 2214.

    CAS  Google Scholar 

  5. Young, M. R. I., Newby, M., & Wepsic, T. H. (1987). Hematopoiesis and suppressor bone marrow cells in mice bearing large metastatic Lewis lung carcinoma tumors. Cancer Research, 47, 100–106.

    CAS  PubMed  Google Scholar 

  6. Subiza, J., Vinuela, J., Rodriguez, R., & De la Concha, E. (1989). Development of splenic natural suppressor (NS) cells in Ehrlich tumor-bearing mice. International Journal of Cancer, 44, 307–314.

    CAS  Google Scholar 

  7. Bronte, V., Apolloni, E., Cabrelle, A., Ronca, R., Serafini, P., & Zamboni, P., et al. (2000). Identification of a CD11b(+)/Gr-1(+)/CD31(+) myeloid progenitor capable of activating or suppressing CD8(+) T cells. Blood, 96, 3838.

    CAS  PubMed  Google Scholar 

  8. Li, Q., Pan, P. Y., Gu, P., Xu, D., & Chen, S. H. (2004). Role of immature myeloid Gr-1+ cells in the development of antitumor immunity. Cancer Research, 64, 1130–1139.

    Article  CAS  PubMed  Google Scholar 

  9. Otsuji, M., Kimura, Y., Aoe, T., Okamoto, Y., & Saito, T. (1996). Oxidative stress by tumor-derived macrophages suppresses the expression of CD3 zeta chain of T-cell receptor complex and antigen-specific T-cell responses. Proceedings of the National Academy of Sciences of the United States of America, 93, 13119–13124.

    Article  CAS  PubMed  Google Scholar 

  10. Gabrilovich, D. I., Velders, M., Sotomayor, E., & Kast, W. M. (2001). Mechanism of immune dysfunction in cancer mediated by immature Gr-1+ myeloid cells. Journal of Immunology, 166, 5398–5406.

    CAS  Google Scholar 

  11. Bronte, V., Serafini, P., De Santo, C., Marigo, I., Tosello, V., & Mazzoni, A., et al. (2003). IL-4-induced arginase 1 suppresses alloreactive T cells in tumor-bearing mice. Journal of Immunology, 170, 270–278.

    CAS  Google Scholar 

  12. Almand, B., Clark, J. I., Nikitina, E., English, N. R., Knight, S. C., & Carbone, D. P., et al. (2001). Increased production of immature myeloid cells in cancer patients. A mechanism of immunosuppression in cancer. Journal of Immunology, 166, 678–689.

    CAS  Google Scholar 

  13. Almand, B., Resser, J., Lindman, B., Nadaf, S., Clark, J., & Kwon, E., et al. (2000). Clinical significance of defective dendritic cell differentiation in cancer. Clinical Cancer Research, 6, 1755–1766.

    CAS  PubMed  Google Scholar 

  14. Bronte, V., Chappell, D. B., Apolloni, E., Cabrelle, A., Wang, M., & Hwu, P., et al. (1999). Unopposed production of granulocyte–macrophage colony-stimulating factor by tumors inhibits CD8+ T cell responses by dysregulating antigen-presenting cell maturation. Journal of Immunology, 162, 5728–5737.

    CAS  Google Scholar 

  15. Nefedova, Y., Huang, M., Kusmartsev, S., Bhattacharya, R., Cheng, P., & Salup, R., et al. (2004). Hyperactivation of STAT3 is involved in abnormal differentiation of dendritic cells in cancer. Journal of Immunology, 172, 464–474.

    CAS  Google Scholar 

  16. Kusmartsev, S., & Gabrilovich, D. I. (2003). Inhibition of myeloid cell differentiation in cancer: The role of reactive oxygen species. Journal of Leukocyte Biology, 74, 186–196.

    Article  CAS  PubMed  Google Scholar 

  17. Gabrilovich, D. I., Chen, H. L., Girgis, K. R., Cunningham, T., Meny, G. M., & Nadaf, S., et al. (1996). Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nature Medicine, 2, 1096–1103.

    Article  CAS  PubMed  Google Scholar 

  18. Kusmartsev, S., & Gabrilovich, D. (2005). STAT1 signaling regulates tumor-associated macrophage-mediated T cell deletion. Journal of Immunology, 174, 4880–4891.

    CAS  Google Scholar 

  19. Toi, M., Kondo, S., Suzuki, H., Yamamoto, Y., Inada, K., & Imazawa, T., et al. (1996). Quantitative analysis of vascular endothelial growth factor in primary breast cancer. Cancer, 77, 1101–1106.

    Article  CAS  PubMed  Google Scholar 

  20. Saito, H., Tsujitani, S., Ikeguchi, M., Maeta, M., & Kaibara, N. (1998). Relationship between the expression of vascular endothelial growth factor and the density of dendritic cells in gastric carcinoma tissue. British Journal of Cancer, 78, 1573.

    CAS  PubMed  Google Scholar 

  21. Gabrilovich, D., Ishida, T., Oyama, T., Ran, S., Kravtsov, V., & Nadaf, S., et al. (1998). Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood, 92, 4150–4166.

    CAS  PubMed  Google Scholar 

  22. Ohm, J. E., Shurin, M. R., Esche, C., Lotze, M. T., & Carbone, D. P., et al. (1999). Effect of vascular endothelial growth factor and FLT3 ligand on dendritic cell generation in vivo. Journal of Immunology, 163, 3260–3268.

    CAS  Google Scholar 

  23. Gabrilovich, D. I., Ishida, T., Nadaf, S., Ohm, J., & Carbone, D. P. (1998). Antibodies to vascular endothelial growth factor enhance the efficacy of cancer immunotherapy by improving endogenous dendritic cell function. Clinical Cancer Research, 5, 2963–2970.

    Google Scholar 

  24. Ishida, T., Oyama, T., Carbone, D., & Gabrilovich, D. I. (1998). Defective function of Langerhans cells in tumor-bearing animals is the result of defective maturation from hematopoietic progenitors. Journal of Immunology, 161, 4842–4851.

    CAS  Google Scholar 

  25. Dikov, M., Ohm, J., Ray, N., Tchekneva, E., Burlison, J., & Moghanaki, D., et al. (2005). Differential roles of vascular endothelial growth factor receptors 1 and 2 in dendritic cell differentiation. Journal of Immunology, 174, 215–222.

    CAS  Google Scholar 

  26. Takahashi, A., Kono, K., Ichihara, F., Sugai, H., Fujii, H., & Matsumoto, Y. (2004). Vascular endothelial growth factor inhibits maturation of dendritic cells induced by lipopolysaccharide, but not by proinflammatory cytokines. Cancer Immunol Immunother, 53, 543–550.

    Article  CAS  PubMed  Google Scholar 

  27. Serafini, P., Carbley, R., Noonan, K. A., Tan, G., Bronte, V., & Borrello, I. (2004). High-dose GM-CSF-producing vaccines impair the immune response through the recruitment of myeloid suppressor cells. Cancer Research, 64, 6337–6343.

    Article  CAS  PubMed  Google Scholar 

  28. Young, M. R., & Lathers, D. M. (1999). Myeloid progenitor cells mediate immune suppression in patients with head and neck cancers. International Journal of Immunopharmacology, 21, 241–252.

    Article  CAS  PubMed  Google Scholar 

  29. Fu, Y., Watson, G., Jimenez, J., Wang, Y., & Lopez, D. (1990). Expansion of immunoregulatory macrophages by granulocyte–macrophage colonystimulating factor derived from a murine mammary tumor. Cancer Research, 50, 227.

    CAS  PubMed  Google Scholar 

  30. Young, M., Wright, M., & Young, M. (1991). Antibodies to colony-stimulating factors block Lewis lung carcinoma cell stimulation of immune-suppressive bone marrow cells. Cancer Immunol Immunother, 33, 146.

    Article  CAS  PubMed  Google Scholar 

  31. Dranoff, G. (2003). GM-CSF-secreting melanoma vaccines. Oncogene, 22, 3188–3192.

    Article  CAS  PubMed  Google Scholar 

  32. Seo, N., Hayakawa, S., Takigawa, M., & Tokura, Y. (2001). Interleukin-10 expressed at early tumour sites induces subsequent generation of CD4(+) T-regulatory cells and systemic collapse of antitumour immunity. Immunology, 103, 449–457.

    Google Scholar 

  33. Yang, A. S., & Lattime, E. C. (2003). Tumor-induced interleukin 10 suppresses the ability of splenic dendritic cells to stimulate CD4 and CD8 T-cell responses. Cancer Research, 63, 2150–2157.

    CAS  PubMed  Google Scholar 

  34. Steinbrink, K., Wolfl, M., Jonuleit, H., Knop, J., & Enk, A. H. (1997). Induction of tolerance by IL-10-treated dendritic cells. Journal of Immunology, 159, 4772–4780.

    CAS  Google Scholar 

  35. Sharma, S., Stolina, M., Lin, Y., Gardner, B., Miller, P., & Kronenberg, M., et al. (1999). T-cell-derived IL-10 promotes lung cancer growth by suppressing both T cell and APC function. Journal of Immunology, 163, 5020.

    CAS  Google Scholar 

  36. Steinbrink, K., Graulich, E., Kubsch, S., Knop, J., & Enk, A. (2002). CD4(+) and CD8(+) anergy T cells induced by interleukin-10-treated human dendritic cells display antigen-specific suppressor activity. Blood, 99, 2468–2476.

    Article  CAS  PubMed  Google Scholar 

  37. Allavena, P., Piemonti, L., Longoni, D., Bernasconi, S., Stoppaciaro, A., & Ruco, L., et al. (1998). IL-10 prevents the differentiation of monocytes to dendritic cells but promotes their maturation to macrophages. European Journal of Immunology, 28, 359–363.

    Article  CAS  PubMed  Google Scholar 

  38. Mullins, D., Martins, R., Burger, C., & Elgert, K. (2001). Tumor cell-derived TGF-beta and IL-10 dysregulate paclitaxel-induced macrophage activation. Journal of Leukocyte Biology, 69, 129–137.

    CAS  PubMed  Google Scholar 

  39. Harizi, H., Juzan, M., Pitard, V., Moreau, J., & Gualde, N. (2002). Cyclooxygenase-2-issued prostaglandin e(2) enhances the production of endogenous IL-10, which down-regulates dendritic cell functions. Journal of Immunology, 68, 2255–2263.

    Google Scholar 

  40. Enk, A. H., Angeloni, V. L., Udey, M. C., & Katz, S. I. (1993). Inhibition of Langerhans cell antigen-presenting function by IL-10. A role for IL-10 in induction of tolerance. Journal of Immunology, 151, 2390–2398.

    CAS  Google Scholar 

  41. Peguet Navarro, J., Moulon, C., Caux, C., Dalbiez-Gauthier, C., Banchereau, J., & Schmitt, D. (1994). Interleukin-10 inhibits the primary allogeneic T cell response to human epidermal Langerhans cells. European Journal of Immunology, 24, 884–889.

    CAS  PubMed  Google Scholar 

  42. Beissert, S., Hosoi, J., Grabbe, S., Asahina, A., & Granstein, R. D. (1995). IL-10 inhibits tumor antigen presentation by epidermal antigen-presenting cells. Journal of Immunology, 154, 1280–1286.

    CAS  Google Scholar 

  43. Caux, C., Massacrier, C., Vanbervliet, B., Barthelemy, C., Liu, Y. J., & Banchereau, J. (1994). Interleukin 10 inhibits T cell alloreaction induced by human dendritic cells. Intern. Immunol., 6, 1177–1185.

    CAS  Google Scholar 

  44. Berman, R. M., Suzuki, T., Tahara, H., Robbins, P. D., Narula, S. K., & Lotze, M. T. (1996). Systemic administration of cellular IL-10 induces an effective, specific, and long-lived immune response against established tumors in mice. Journal of Immunology, 157, 231–238.

    CAS  Google Scholar 

  45. Menetrier-Caux, C., Montmain, G., Dieu, M., Bain, C., Favrot, M., & Caux, C., et al. (1998). Inhibition of the differentiation of dendritic cells from CD34(+) progenitors by tumor cells: Role of interleukin-6 and macrophage-colony-stimulating factor. Blood, 92, 4778.

    CAS  PubMed  Google Scholar 

  46. Menetrier-Caux, C., Thomachot, M. C., Alberti, L., Montmain, G., & Blay, J. Y. (2001). IL-4 prevents the blockade of dendritic cell differentiation induced by tumor cells. Cancer Research, 61, 3096–3104.

    CAS  PubMed  Google Scholar 

  47. Park, S. J., Nakagawa, T., Kitamura, H., Atsumi, T., Kamon, H., & Sawa, S., et al. (2004). IL-6 regulates in vivo dendritic cell differentiation through STAT3 activation. Journal of Immunology, 173, 3844–3854.

    CAS  Google Scholar 

  48. Ratta, M., Fagnoni, F., Curti, A., Vescovini, R., Sansoni, P., & Oliviero, B., et al. (2002). Dendritic cells are functionally defective in multiple myeloma: The role of interleukin-6. Blood, 100, 230–237.

    Article  CAS  PubMed  Google Scholar 

  49. Hayashi, T., Hideshima, T., Akiyama, M., Raje, N., Richardson, P., & Chauhan, D., et al. (2003). Ex vivo induction of multiple myeloma-specific cytotoxic T lymphocytes. Blood, 102, 1435–1442.

    Article  CAS  PubMed  Google Scholar 

  50. Hakomori, S. (2003). Structure, organization, and function of glycosphingolipids in membrane. Current Opinion in Hematology, 10, 16–24.

    Article  CAS  PubMed  Google Scholar 

  51. Birkle, S., Zeng, G., Gao, L., Yu, R. K., & Aubry, J. (2003). Role of tumor-associated gangliosides in cancer progression. Biochimie, 85, 455–463.

    Article  CAS  PubMed  Google Scholar 

  52. Shurin, G. V., Shurin, M. R., Bykovskaia, S., Shogan, J., Lotze, M. T., & Barksdale, E. M., Jr. (2001). Neuroblastoma-derived gangliosides inhibit dendritic cell generation and function. Cancer Research, 61, 363–369.

    CAS  PubMed  Google Scholar 

  53. Peguet-Navarro, J., Sportouch, M., Popa, I., Berthier, O., Schmitt, D., & Portoukalian, J. (2003). Gangliosides from human melanoma tumors impair dendritic cell differentiation from monocytes and induce their apoptosis. Journal of Immunology, 170, 3488–3494.

    CAS  Google Scholar 

  54. Sombroek, C., Stam, A., Masterson, A., Lougheed, S., Schakel, M., & Meijer, C., et al. (2002). Prostanoids play a major role in the primary tumor-induced inhibition of dendritic cell differentiation. Journal of Immunology, 168, 4333–4343.

    CAS  Google Scholar 

  55. Yang, L., Yamagata, N., Yadav, R., Brandon, S., Courtney, R., & Morrow, J., et al. (2003). Cancer-associated immunodeficiency and dendritic cell abnormalities mediated by the prostaglandin EP2 receptor. Journal of Clinical Investigation, 111, 727–735.

    Article  CAS  PubMed  Google Scholar 

  56. Young, M., Wright, M., Coogan, M., Young, M., and Bagash, J. (1992). Tumor-derived cytokines induce bone marrow suppressor cells that mediate immunosuppression through transforming growth factor beta. Cancer Immunol Immunother, 35, 14–18.

    Article  CAS  PubMed  Google Scholar 

  57. Alleva, D., Walker, T., & Elgert, K. (1995). Induction of macrophage suppressor activity by fibrosarcoma-derived transforming growth factor-beta 1: Contrasting effects on resting and activated macrophages. Journal of Leukocyte Biology, 57, 919–928.

    Google Scholar 

  58. Maeda, H., & Shiraishi, A. (1996). TGF-beta contributes to the shift toward Th2-type responses through direct and IL-10-mediated pathways in tumor-bearing mice. Journal of Immunology, 156, 73–78.

    CAS  Google Scholar 

  59. Reeves, E., Lu, H., Jacobs, H., Messina, C., Bolsover, S., & Gabella, G., et al. (2002). Killing activity of neutrophils is mediated through activation of proteases by K+ flux. Nature, 416, 291–297.

    Google Scholar 

  60. Schmielau, J., & Finn, O. J. (2001). Activated granulocytes and granulocyte-derived hydrogen peroxide are the underlying mechanism of suppression of t-cell function in advanced cancer patients. Cancer Research, 61, 4756–4760.

    CAS  PubMed  Google Scholar 

  61. Kusmartsev, S., Nefedova, Y., Yoder, D., & Gabrilovich, D. I. (2004). Antigen-specific inhibition of CD8+ T cell response by immature myeloid cells in cancer is mediated by reactive oxygen species. Journal of Immunology, 172, 989–999.

    CAS  Google Scholar 

  62. Sauer, H., Wartenberg, M., & Hescheler, J. (2001). Reactive oxygen species as intracellular messengers during cell growth and differentiation. Cellular Physiology and Biochemistry, 11, 173–186.

    Article  CAS  PubMed  Google Scholar 

  63. Rane, S. G., & Reddy, E. S. (2000). Janus kinases: Components of multiple signaling pathways. Oncogene, 19, 5662–5679.

    Article  CAS  PubMed  Google Scholar 

  64. Imada, K. & Leonard, W. J. (2000). The JAK-STAT pathway. Molecular Immunology, 37, 1–11.

    Article  CAS  PubMed  Google Scholar 

  65. Nosaka, T., & Kitamura, T. (2000). Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) in hematopoietic cells. International Journal of Hematology, 71, 309–319.

    CAS  PubMed  Google Scholar 

  66. Steelman, L. S., Pohnert, S. C., Shelton, J. G., Franklin, R. A., Bertrand, F. E., & McCubrey, J. A. (2004). JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia, 18, 189–218.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  68. Wang, T., Niu, G., Kortylewski, M., Burdelya, L., Shain, K., & Zhang, S., et al. (2004). Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Natural Medicines, 10, 48–54.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. H. Lee Moffitt Cancer Center, University of South Florida, MRC 2067, 12902 Magnolia Dr, Tampa, FL, 33612, USA

    Sergei Kusmartsev & Dmitry I. Gabrilovich

Authors
  1. Sergei Kusmartsev
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dmitry I. Gabrilovich
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dmitry I. Gabrilovich.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kusmartsev, S., Gabrilovich, D.I. Effect of tumor-derived cytokines and growth factors on differentiation and immune suppressive features of myeloid cells in cancer. Cancer Metastasis Rev 25, 323–331 (2006). https://doi.org/10.1007/s10555-006-9002-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-006-9002-6

Keywords

Search

Navigation