Skip to main content

Advertisement

SpringerLink
Log in

Angiogenesis and immunity: a bidirectional link potentially relevant for the monitoring of antiangiogenic therapy and the development of novel therapeutic combination with immunotherapy

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

Abstract

The immune system regulates angiogenesis in cancer with both pro- and antiangiogenic activities. The induction of angiogenesis is mediated by tumor-associated macrophages and myeloid-derived suppressor cells (MDSC) which produce proinflammatory cytokines, endothelial growth factors (VEGF, bFGF…), and protease (MMP9) implicated in neoangiogenesis. Some cytokines (IL-6, IL-17…) activated Stat3 which also led to the production of VEGF and bFGF. In contrast, other cytokines (IFN, IL-12, IL-21, and IL-27) display an antiangiogenic activity. Recently, it has been shown that some antiangiogenic molecules alleviates immunosuppression associated with cancer by decreasing immunosuppressive cells (MDSC, regulatory T cells), immunosuppressive cytokines (IL-10, TGFβ), and inhibitory molecules on T cells (PD-1). Some of these broad effects may result from the ability of some antiangiogenic molecules, especially cytokines to inhibit the Stat3 transcription factor. The association often observed between angiogenesis and immunosuppression may be related to hypoxia which induces both neoangiogenesis via activation of HIF-1 and VEGF and favors the intratumor recruitment and differentiation of regulatory T cells and MDSC. Preliminary studies suggest that modulation of immune markers (intratumoral MDSC and IL-8, peripheral regulatory T cells…) may predict clinical response to antiangiogenic therapy. In preclinical models, a synergy has been observed between antiangiogenic molecules and immunotherapy which may be explained by an improvement of immune status in tumor-bearing mice after antiangiogenic therapy. In preclinical models, antiangiogenic molecules promoted intratumor trafficking of effector cells, enhance endogenous anti-tumor response, and synergyzed with immunotherapy protocols to cure established murine tumors. All these results warrant the development of clinical trials combining antiangiogenic drugs and immunotherapy.

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

Fig. 1

Similar content being viewed by others

References

  1. Oudard, S., George, D., Medioni, J., & Motzer, R. (2007). Treatment options in renal cell carcinoma: Past, present and future. Annals of Oncology, 18(Suppl 10), x25–x31.

    PubMed  Google Scholar 

  2. Rini, B. I., Campbell, S. C., & Escudier, B. (2009). Renal cell carcinoma. Lancet, 373, 1119–1132.

    PubMed  CAS  Google Scholar 

  3. Oudard, S., Medioni, J., Aylllon, J., Barrascourt, E., Elaidi, R. T., Balcaceres, J., et al. (2009). Everolimus (RAD001): An mTOR inhibitor for the treatment of metastatic renal cell carcinoma. Expert Review of Anticancer Therapy, 9, 705–717.

    PubMed  CAS  Google Scholar 

  4. Motzer, R. J., Hutson, T. E., Tomczak, P., Michaelson, M. D., Bukowski, R. M., Rixe, O., et al. (2007). Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. The New England Journal of Medicine, 356, 115–124.

    PubMed  CAS  Google Scholar 

  5. Barrascout, E., Medioni, J., Scotte, F., Ayllon, J., Mejean, A., Cuenod, C. A., et al. (2010). Angiogenesis inhibition: Review of the activity of sorafenib, sunitinib and bevacizumab. Bulletin du Cancer, 97, 29–43.

    PubMed  CAS  Google Scholar 

  6. Escudier, B., Bellmunt, J., Negrier, S., Bajetta, E., Melichar, B., Bracarda, S., et al. (2010). Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): Final analysis of overall survival. Journal of Clinical Oncology, 28, 2144–2150.

    PubMed  CAS  Google Scholar 

  7. Rini, B. I., Halabi, S., Rosenberg, J. E., Stadler, W. M., Vaena, D. A., Archer, L., et al. (2010). Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: Final results of CALGB 90206. Journal of Clinical Oncology, 28, 2137–2143.

    PubMed  CAS  Google Scholar 

  8. Motzer, R. J., Escudier, B., Oudard, S., Hutson, T. E., Porta, C., Bracarda, S., et al. (2008). Efficacy of everolimus in advanced renal cell carcinoma: A double-blind, randomised, placebo-controlled phase III trial. Lancet, 372, 449–456.

    PubMed  CAS  Google Scholar 

  9. Van Meter, M. E., & Kim, E. S. (2010). Bevacizumab: Current updates in treatment. Current Opinion in Oncology, 22, 586–591.

    PubMed  Google Scholar 

  10. Paez-Ribes, M., Allen, E., Hudock, J., Takeda, T., Okuyama, H., Vinals, F., et al. (2009). Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell, 15, 220–231.

    PubMed  CAS  Google Scholar 

  11. Ebos, J. M., Lee, C. R., Cruz-Munoz, W., Bjarnason, G. A., Christensen, J. G., & Kerbel, R. S. (2009). Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell, 15, 232–239.

    PubMed  CAS  Google Scholar 

  12. Rini, B. I., & Flaherty, K. (2008). Clinical effect and future considerations for molecularly-targeted therapy in renal cell carcinoma. Urologic Oncology, 26, 543–549.

    PubMed  CAS  Google Scholar 

  13. Albini, A., Tosetti, F., Benelli, R., & Noonan, D. M. (2005). Tumor inflammatory angiogenesis and its chemoprevention. Cancer Research, 65, 10637–10641.

    PubMed  CAS  Google Scholar 

  14. de Visser, K. E., Eichten, A., & Coussens, L. M. (2006). Paradoxical roles of the immune system during cancer development. Nature Reviews. Cancer, 6, 24–37.

    PubMed  Google Scholar 

  15. Murdoch, C., Muthana, M., Coffelt, S. B., & Lewis, C. E. (2008). The role of myeloid cells in the promotion of tumour angiogenesis. Nature Reviews. Cancer, 8, 618–631.

    PubMed  CAS  Google Scholar 

  16. Sunderkotter, C., Steinbrink, K., Goebeler, M., Bhardwaj, R., & Sorg, C. (1994). Macrophages and angiogenesis. Journal of Leukocyte Biology, 55, 410–422.

    PubMed  CAS  Google Scholar 

  17. Kimura, Y. N., Watari, K., Fotovati, A., Hosoi, F., Yasumoto, K., Izumi, H., et al. (2007). Inflammatory stimuli from macrophages and cancer cells synergistically promote tumor growth and angiogenesis. Cancer Science, 98, 2009–2018.

    PubMed  CAS  Google Scholar 

  18. Lewis, C. E., Leek, R., Harris, A., & McGee, J. O. (1995). Cytokine regulation of angiogenesis in breast cancer: The role of tumor-associated macrophages. Journal of Leukocyte Biology, 57, 747–751.

    PubMed  CAS  Google Scholar 

  19. Mantovani, A., Schioppa, T., Porta, C., Allavena, P., & Sica, A. (2006). Role of tumor-associated macrophages in tumor progression and invasion. Cancer and Metastasis Reviews, 25, 315–322.

    PubMed  Google Scholar 

  20. Grunewald, M., Avraham, I., Dor, Y., Bachar-Lustig, E., Itin, A., Jung, S., et al. (2006). VEGF-induced adult neovascularization: Recruitment, retention, and role of accessory cells. Cell, 124, 175–189.

    PubMed  CAS  Google Scholar 

  21. Du, R., Lu, K. V., Petritsch, C., Liu, P., Ganss, R., Passegue, E., et al. (2008). HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell, 13, 206–220.

    PubMed  CAS  Google Scholar 

  22. Giraudo, E., Inoue, M., & Hanahan, D. (2004). An amino-bisphosphonate targets MMP-9-expressing macrophages and angiogenesis to impair cervical carcinogenesis. The Journal of Clinical Investigation, 114, 623–633.

    PubMed  CAS  Google Scholar 

  23. Neufeld, G., & Kessler, O. (2006). Pro-angiogenic cytokines and their role in tumor angiogenesis. Cancer and Metastasis Reviews, 25, 373–385.

    PubMed  CAS  Google Scholar 

  24. Kim, Y. M., Lee, Y. M., Kim, H. S., Kim, J. D., Choi, Y., Kim, K. W., et al. (2002). TNF-related activation-induced cytokine (TRANCE) induces angiogenesis through the activation of Src and phospholipase C (PLC) in human endothelial cells. The Journal of Biological Chemistry, 277, 6799–6805.

    PubMed  CAS  Google Scholar 

  25. Silva-Santos, B. (2010). Promoting angiogenesis within the tumor microenvironment: The secret life of murine lymphoid IL-17-producing gammadelta T cells. European Journal of Immunology, 40, 1873–1876.

    PubMed  CAS  Google Scholar 

  26. Numasaki, M., Fukushi, J., Ono, M., Narula, S. K., Zavodny, P. J., Kudo, T., et al. (2003). Interleukin-17 promotes angiogenesis and tumor growth. Blood, 101, 2620–2627.

    PubMed  CAS  Google Scholar 

  27. Zou, W., & Restifo, N. P. (2010). T(H)17 cells in tumour immunity and immunotherapy. Nature Reviews. Immunology, 10, 248–256.

    PubMed  CAS  Google Scholar 

  28. Numasaki, M., Watanabe, M., Suzuki, T., Takahashi, H., Nakamura, A., McAllister, F., et al. (2005). IL-17 enhances the net angiogenic activity and in vivo growth of human non-small cell lung cancer in SCID mice through promoting CXCR-2-dependent angiogenesis. Journal of Immunology, 175, 6177–6189.

    CAS  Google Scholar 

  29. Ciree, A., Michel, L., Camilleri-Broet, S., Jean Louis, F., Oster, M., Flageul, B., et al. (2004). Expression and activity of IL-17 in cutaneous T-cell lymphomas (mycosis fungoides and Sezary syndrome). International Journal of Cancer, 112, 113–120.

    CAS  Google Scholar 

  30. Pickens, S. R., Volin, M. V., Mandelin, A. M., 2nd, Kolls, J. K., Pope, R. M., & Shahrara, S. (2010). IL-17 contributes to angiogenesis in rheumatoid arthritis. Journal of Immunology, 184, 3233–3241.

    CAS  Google Scholar 

  31. Kuniyasu, H., Ohmori, H., Sasaki, T., Sasahira, T., Yoshida, K., Kitadai, Y., et al. (2003). Production of interleukin 15 by human colon cancer cells is associated with induction of mucosal hyperplasia, angiogenesis, and metastasis. Clinical Cancer Research, 9, 4802–4810.

    PubMed  CAS  Google Scholar 

  32. Badoual, C., Bouchaud, G., Agueznay Nel, H., Mortier, E., Hans, S., Gey, A., et al. (2008). The soluble alpha chain of interleukin-15 receptor: A proinflammatory molecule associated with tumor progression in head and neck cancer. Cancer Research, 68, 3907–3914.

    PubMed  CAS  Google Scholar 

  33. Yu, H., Kortylewski, M., & Pardoll, D. (2007). Crosstalk between cancer and immune cells: Role of STAT3 in the tumour microenvironment. Nature Reviews. Immunology, 7, 41–51.

    PubMed  CAS  Google Scholar 

  34. Badoual, C., Sandoval, F., Pere, H., Hans, S., Gey, A., Merillon, N., et al. (2010). Better understanding tumor-host interaction in head and neck cancer to improve the design and development of immunotherapeutic strategies. Head & Neck, 32, 946–958.

    Google Scholar 

  35. Voest, E. E., Kenyon, B. M., O’Reilly, M. S., Truitt, G., D’Amato, R. J., & Folkman, J. (1995). Inhibition of angiogenesis in vivo by interleukin 12. Journal of the National Cancer Institute, 87, 581–586.

    PubMed  CAS  Google Scholar 

  36. Sgadari, C., Angiolillo, A. L., & Tosato, G. (1996). Inhibition of angiogenesis by interleukin-12 is mediated by the interferon-inducible protein 10. Blood, 87, 3877–3882.

    PubMed  CAS  Google Scholar 

  37. Haicheur, N., Escudier, B., Dorval, T., Negrier, S., De Mulder, P. H., Dupuy, J. M., et al. (2000). Cytokines and soluble cytokine receptor induction after IL-12 administration in cancer patients. Clinical and Experimental Immunology, 119, 28–37.

    PubMed  CAS  Google Scholar 

  38. Dias, S., Boyd, R., & Balkwill, F. (1998). IL-12 regulates VEGF and MMPs in a murine breast cancer model. International Journal of Cancer, 78, 361–365.

    CAS  Google Scholar 

  39. Dinney, C. P., Bielenberg, D. R., Perrotte, P., Reich, R., Eve, B. Y., Bucana, C. D., et al. (1998). Inhibition of basic fibroblast growth factor expression, angiogenesis, and growth of human bladder carcinoma in mice by systemic interferon-alpha administration. Cancer Research, 58, 808–814.

    PubMed  CAS  Google Scholar 

  40. Mitola, S., Strasly, M., Prato, M., Ghia, P., & Bussolino, F. (2003). IL-12 regulates an endothelial cell-lymphocyte network: Effect on metalloproteinase-9 production. Journal of Immunology, 171, 3725–3733.

    CAS  Google Scholar 

  41. Shimizu, M., Shimamura, M., Owaki, T., Asakawa, M., Fujita, K., Kudo, M., et al. (2006). Antiangiogenic and antitumor activities of IL-27. Journal of Immunology, 176, 7317–7324.

    CAS  Google Scholar 

  42. Castermans, K., Tabruyn, S. P., Zeng, R., van Beijnum, J. R., Eppolito, C., Leonard, W. J., et al. (2008). Angiostatic activity of the antitumor cytokine interleukin-21. Blood, 112, 4940–4947.

    PubMed  CAS  Google Scholar 

  43. Tartour, E., Mathiot, C., & Fridman, W. H. (1992). Current status of interleukin-2 therapy in cancer. Biomedicine & Pharmacotherapy, 46, 473–484.

    CAS  Google Scholar 

  44. Ellis, L. M., & Hicklin, D. J. (2008). VEGF-targeted therapy: Mechanisms of anti-tumour activity. Nature Reviews. Cancer, 8, 579–591.

    PubMed  CAS  Google Scholar 

  45. Belkaid, Y., & Oldenhove, G. (2008). Tuning microenvironments: Induction of regulatory T cells by dendritic cells. Immunity, 29, 362–371.

    PubMed  CAS  Google Scholar 

  46. Curiel, T. J. (2007). Tregs and rethinking cancer immunotherapy. The Journal of Clinical Investigation, 117, 1167–1174.

    PubMed  CAS  Google Scholar 

  47. Oyama, T., Ran, S., Ishida, T., Nadaf, S., Kerr, L., Carbone, D. P., et al. (1998). Vascular endothelial growth factor affects dendritic cell maturation through the inhibition of nuclear factor-kappa B activation in hemopoietic progenitor cells. Journal of Immunology, 160, 1224–1232.

    CAS  Google Scholar 

  48. Dikov, M. M., Ohm, J. E., Ray, N., Tchekneva, E. 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 

  49. Gabrilovich, D. I., Ishida, T., Nadaf, S., Ohm, J. E., & Carbone, D. P. (1999). Antibodies to vascular endothelial growth factor enhance the efficacy of cancer immunotherapy by improving endogenous dendritic cell function. Clinical Cancer Research, 5, 2963–2970.

    PubMed  CAS  Google Scholar 

  50. Batchelor, T. T., Sorensen, A. G., di Tomaso, E., Zhang, W. T., Duda, D. G., Cohen, K. S., et al. (2007). AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell, 11, 83–95.

    PubMed  CAS  Google Scholar 

  51. Laxmanan, S., Robertson, S. W., Wang, E., Lau, J. S., Briscoe, D. M., & Mukhopadhyay, D. (2005). Vascular endothelial growth factor impairs the functional ability of dendritic cells through Id pathways. Biochemical and Biophysical Research Communications, 334, 193–198.

    PubMed  CAS  Google Scholar 

  52. Ohm, J. E., Shurin, M. R., Esche, C., Lotze, M. T., Carbone, D. P., & Gabrilovich, D. I. (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 

  53. Gabrilovich, D. I., Chen, H. L., Girgis, K. R., Cunningham, H. 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. Natural Medicines, 2, 1096–1103.

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  55. Osada, T., Chong, G., Tansik, R., Hong, T., Spector, N., Kumar, R., et al. (2008). The effect of anti-VEGF therapy on immature myeloid cell and dendritic cells in cancer patients. Cancer Immunology, Immunotherapy, 57, 1115–1124.

    PubMed  CAS  Google Scholar 

  56. Fricke, I., Mirza, N., Dupont, J., Lockhart, C., Jackson, A., Lee, J. H., et al. (2007). Vascular endothelial growth factor-trap overcomes defects in dendritic cell differentiation but does not improve antigen-specific immune responses. Clinical Cancer Research, 13, 4840–4848.

    PubMed  CAS  Google Scholar 

  57. Strauss, L., Volland, D., Kunkel, M., & Reichert, T. E. (2005). Dual role of VEGF family members in the pathogenesis of head and neck cancer (HNSCC): Possible link between angiogenesis and immune tolerance. Medical Science Monitor, 11, BR280–292.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  59. Boissel, N., Rousselot, P., Raffoux, E., Cayuela, J. M., Maarek, O., Charron, D., et al. (2004). Defective blood dendritic cells in chronic myeloid leukemia correlate with high plasmatic VEGF and are not normalized by imatinib mesylate. Leukemia, 18, 1656–1661.

    PubMed  CAS  Google Scholar 

  60. Finke, J. H., Rini, B., Ireland, J., Rayman, P., Richmond, A., Golshayan, A., et al. (2008). Sunitinib reverses type-1 immune suppression and decreases T-regulatory cells in renal cell carcinoma patients. Clinical Cancer Research, 14, 6674–6682.

    PubMed  CAS  Google Scholar 

  61. Hipp, M. M., Hilf, N., Walter, S., Werth, D., Brauer, K. M., Radsak, M. P., et al. (2008). Sorafenib, but not sunitinib, affects function of dendritic cells and induction of primary immune responses. Blood, 111, 5610–5620.

    PubMed  CAS  Google Scholar 

  62. Adotevi, O., Pere, H., Ravel, P., Haicheur, N., Badoual, C., Merillon, N., et al. (2010). A decrease of regulatory T cells correlates with overall survival after sunitinib-based antiangiogenic therapy in metastatic renal cancer patients. J Immunother, 33, 991–998.

    Google Scholar 

  63. Abe, F., Younos, I., Westphal, S., Samson, H., Scholar, E., Dafferner, A., et al. (2010). Therapeutic activity of sunitinib for Her2/neu induced mammary cancer in FVB mice. International Immunopharmacology, 10, 140–145.

    PubMed  CAS  Google Scholar 

  64. Badoual, C., Hans, S., Rodriguez, J., Peyrard, S., Klein, C., Agueznay Nel, H., et al. (2006). Prognostic value of tumor-infiltrating CD4+ T-cell subpopulations in head and neck cancers. Clinical Cancer Research, 12, 465–472.

    PubMed  CAS  Google Scholar 

  65. Badoual, C., Hans, S., Fridman, W. H., Brasnu, D., Erdman, S., & Tartour, E. (2009). Revisiting the prognostic value of regulatory T cells in patients with cancer. Journal of Clinical Oncology, 27, e5–6. author reply e7.

    PubMed  Google Scholar 

  66. Suzuki, H., Onishi, H., Wada, J., Yamasaki, A., Tanaka, H., Nakano, K., et al. (2010). VEGFR2 is selectively expressed by FOXP3high CD4+ Treg. European Journal of Immunology, 40, 197–203.

    PubMed  CAS  Google Scholar 

  67. Ko, J. S., Zea, A. H., Rini, B. I., Ireland, J. L., Elson, P., Cohen, P., et al. (2009). Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients. Clinical Cancer Research, 15, 2148–2157.

    PubMed  CAS  Google Scholar 

  68. Huang, B., Pan, P. Y., Li, Q., Sato, A. I., Levy, D. E., Bromberg, J., et al. (2006). Gr-1+CD115+ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-bearing host. Cancer Research, 66, 1123–1131.

    PubMed  CAS  Google Scholar 

  69. 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.

    PubMed  CAS  Google Scholar 

  70. Ohm, J. E., & Carbone, D. P. (2001). VEGF as a mediator of tumor-associated immunodeficiency. Immunologic Research, 23, 263–272.

    PubMed  CAS  Google Scholar 

  71. Shojaei, F., Wu, X., Zhong, C., Yu, L., Liang, X. H., Yao, J., et al. (2007). Bv8 regulates myeloid-cell-dependent tumour angiogenesis. Nature, 450, 825–831.

    PubMed  CAS  Google Scholar 

  72. Pan, P. Y., Wang, G. X., Yin, B., Ozao, J., Ku, T., Divino, C. M., et al. (2008). Reversion of immune tolerance in advanced malignancy: Modulation of myeloid-derived suppressor cell development by blockade of stem-cell factor function. Blood, 111, 219–228.

    PubMed  CAS  Google Scholar 

  73. Curti, A., Fogli, M., Ratta, M., Tura, S., & Lemoli, R. M. (2001). Stem cell factor and FLT3-ligand are strictly required to sustain the long-term expansion of primitive CD34+DR- dendritic cell precursors. Journal of Immunology, 166, 848–854.

    CAS  Google Scholar 

  74. Filipazzi, P., Valenti, R., Huber, V., Pilla, L., Canese, P., Iero, M., et al. (2007). Identification of a new subset of myeloid suppressor cells in peripheral blood of melanoma patients with modulation by a granulocyte-macrophage colony-stimulation factor-based antitumor vaccine. Journal of Clinical Oncology, 25, 2546–2553.

    PubMed  CAS  Google Scholar 

  75. Gabrilovich, D. I., & Nagaraj, S. (2009). Myeloid-derived suppressor cells as regulators of the immune system. Nature Reviews. Immunology, 9, 162–174.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  77. Marigo, I., Dolcetti, L., Serafini, P., Zanovello, P., & Bronte, V. (2008). Tumor-induced tolerance and immune suppression by myeloid derived suppressor cells. Immunological Reviews, 222, 162–179.

    PubMed  CAS  Google Scholar 

  78. Costantino, L., & Barlocco, D. (2008). STAT 3 as a target for cancer drug discovery. Current Medicinal Chemistry, 15, 834–843.

    PubMed  CAS  Google Scholar 

  79. Kortylewski, M., Kujawski, M., Wang, T., Wei, S., Zhang, S., Pilon-Thomas, S., et al. (2005). Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Natural Medicines, 11, 1314–1321.

    CAS  Google Scholar 

  80. Kortylewski, M., & Yu, H. (2008). Role of Stat3 in suppressing anti-tumor immunity. Current Opinion in Immunology, 20, 228–233.

    PubMed  CAS  Google Scholar 

  81. Yu, H., & Jove, R. (2004). The STATs of cancer—New molecular targets come of age. Nature Reviews. Cancer, 4, 97–105.

    PubMed  CAS  Google Scholar 

  82. Xie, T. X., Wei, D., Liu, M., Gao, A. C., Ali-Osman, F., Sawaya, R., et al. (2004). Stat3 activation regulates the expression of matrix metalloproteinase-2 and tumor invasion and metastasis. Oncogene, 23, 3550–3560.

    PubMed  CAS  Google Scholar 

  83. Noman, M. Z., Buart, S., Van Pelt, J., Richon, C., Hasmim, M., Leleu, N., et al. (2009). The cooperative induction of hypoxia-inducible factor-1alpha and STAT3 during hypoxia induced an impairment of tumor susceptibility to CTL-mediated cell lysis. Journal of Immunology, 182, 3510–3521.

    CAS  Google Scholar 

  84. Kujawski, M., Kortylewski, M., Lee, H., Herrmann, A., Kay, H., & Yu, H. (2008). Stat3 mediates myeloid cell-dependent tumor angiogenesis in mice. The Journal of Clinical Investigation, 118, 3367–3377.

    PubMed  CAS  Google Scholar 

  85. Xin, H., Zhang, C., Herrmann, A., Du, Y., Figlin, R., & Yu, H. (2009). Sunitinib inhibition of Stat3 induces renal cell carcinoma tumor cell apoptosis and reduces immunosuppressive cells. Cancer Research, 69, 2506–2513.

    PubMed  CAS  Google Scholar 

  86. Kim, D. W., Jo, Y. S., Jung, H. S., Chung, H. K., Song, J. H., Park, K. C., et al. (2006). An orally administered multitarget tyrosine kinase inhibitor, SU11248, is a novel potent inhibitor of thyroid oncogenic RET/papillary thyroid cancer kinases. The Journal of Clinical Endocrinology and Metabolism, 91, 4070–4076.

    PubMed  CAS  Google Scholar 

  87. Ozao-Choy, J., Ma, G., Kao, J., Wang, G. X., Meseck, M., Sung, M., et al. (2009). The novel role of tyrosine kinase inhibitor in the reversal of immune suppression and modulation of tumor microenvironment for immune-based cancer therapies. Cancer Research, 69, 2514–2522.

    PubMed  CAS  Google Scholar 

  88. Inman, B. A., Frigola, X., Dong, H., & Kwon, E. D. (2007). Costimulation, coinhibition and cancer. Current Cancer Drug Targets, 7, 15–30.

    PubMed  CAS  Google Scholar 

  89. Fox, S. B., Launchbury, R., Bates, G. J., Han, C., Shaida, N., Malone, P. R., et al. (2007). The number of regulatory T cells in prostate cancer is associated with the androgen receptor and hypoxia-inducible factor (HIF)-2alpha but not HIF-1alpha. The Prostate, 67, 623–629.

    PubMed  Google Scholar 

  90. Aghi, M., Cohen, K. S., Klein, R. J., Scadden, D. T., & Chiocca, E. A. (2006). Tumor stromal-derived factor-1 recruits vascular progenitors to mitotic neovasculature, where microenvironment influences their differentiated phenotypes. Cancer Research, 66, 9054–9064.

    PubMed  CAS  Google Scholar 

  91. Ben-Shoshan, J., Maysel-Auslender, S., Mor, A., Keren, G., & George, J. (2008). Hypoxia controls CD4+CD25+ regulatory T-cell homeostasis via hypoxia-inducible factor-1alpha. European Journal of Immunology, 38, 2412–2418.

    PubMed  CAS  Google Scholar 

  92. Dayan, F., Mazure, N. M., Brahimi-Horn, M. C., & Pouyssegur, J. (2008). A dialogue between the hypoxia-inducible factor and the tumor microenvironment. Cancer Microenviron, 1, 53–68.

    PubMed  Google Scholar 

  93. Sitkovsky, M. V., Kjaergaard, J., Lukashev, D., & Ohta, A. (2008). Hypoxia-adenosinergic immunosuppression: Tumor protection by T regulatory cells and cancerous tissue hypoxia. Clinical Cancer Research, 14, 5947–5952.

    PubMed  CAS  Google Scholar 

  94. Harizi, H., Juzan, M., Pitard, V., Moreau, J. F., & 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, 168, 2255–2263.

    CAS  Google Scholar 

  95. Baratelli, F., Lin, Y., Zhu, L., Yang, S. C., Heuze-Vourc’h, N., Zeng, G., et al. (2005). Prostaglandin E2 induces FOXP3 gene expression and T regulatory cell function in human CD4+ T cells. Journal of Immunology, 175, 1483–1490.

    CAS  Google Scholar 

  96. Akasaki, Y., Liu, G., Chung, N. H., Ehtesham, M., Black, K. L., & Yu, J. S. (2004). Induction of a CD4+ T regulatory type 1 response by cyclooxygenase-2-overexpressing glioma. Journal of Immunology, 173, 4352–4359.

    CAS  Google Scholar 

  97. Bergmann, C., Strauss, L., Zeidler, R., Lang, S., & Whiteside, T. L. (2007). Expansion of human T regulatory type 1 cells in the microenvironment of cyclooxygenase 2 overexpressing head and neck squamous cell carcinoma. Cancer Research, 67, 8865–8873.

    PubMed  CAS  Google Scholar 

  98. Rodriguez, P. C., Hernandez, C. P., Quiceno, D., Dubinett, S. M., Zabaleta, J., Ochoa, J. B., et al. (2005). Arginase I in myeloid suppressor cells is induced by COX-2 in lung carcinoma. The Journal of Experimental Medicine, 202, 931–939.

    PubMed  CAS  Google Scholar 

  99. Murakami, A., & Ohigashi, H. (2007). Targeting NOX, INOS and COX-2 in inflammatory cells: Chemoprevention using food phytochemicals. International Journal of Cancer, 121, 2357–2363.

    CAS  Google Scholar 

  100. Gately, S., & Li, W. W. (2004). Multiple roles of COX-2 in tumor angiogenesis: A target for antiangiogenic therapy. Seminars in Oncology, 31, 2–11.

    PubMed  CAS  Google Scholar 

  101. Sharma, S., Yang, S. C., Zhu, L., Reckamp, K., Gardner, B., Baratelli, F., et al. (2005). Tumor cyclooxygenase-2/prostaglandin E2-dependent promotion of FOXP3 expression and CD4+ CD25+ T regulatory cell activities in lung cancer. Cancer Research, 65, 5211–5220.

    PubMed  CAS  Google Scholar 

  102. Haas, A. R., Sun, J., Vachani, A., Wallace, A. F., Silverberg, M., Kapoor, V., et al. (2006). Cycloxygenase-2 inhibition augments the efficacy of a cancer vaccine. Clinical Cancer Research, 12, 214–222.

    PubMed  CAS  Google Scholar 

  103. Greenhough, A., Smartt, H. J., Moore, A. E., Roberts, H. R., Williams, A. C., Paraskeva, C., et al. (2009). The COX-2/PGE2 pathway: Key roles in the hallmarks of cancer and adaptation to the tumour microenvironment. Carcinogenesis, 30, 377–386.

    PubMed  CAS  Google Scholar 

  104. Motzer, R. J., Michaelson, M. D., Redman, B. G., Hudes, G. R., Wilding, G., Figlin, R. A., et al. (2006). Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. Journal of Clinical Oncology, 24, 16–24.

    PubMed  CAS  Google Scholar 

  105. Norden-Zfoni, A., Desai, J., Manola, J., Beaudry, P., Force, J., Maki, R., et al. (2007). Blood-based biomarkers of SU11248 activity and clinical outcome in patients with metastatic imatinib-resistant gastrointestinal stromal tumor. Clinical Cancer Research, 13, 2643–2650.

    PubMed  CAS  Google Scholar 

  106. Dellapasqua, S., Bertolini, F., Bagnardi, V., Campagnoli, E., Scarano, E., Torrisi, R., et al. (2008). Metronomic cyclophosphamide and capecitabine combined with bevacizumab in advanced breast cancer. Journal of Clinical Oncology, 26, 4899–4905.

    PubMed  CAS  Google Scholar 

  107. Bertolini, F., Shaked, Y., Mancuso, P., & Kerbel, R. S. (2006). The multifaceted circulating endothelial cell in cancer: Towards marker and target identification. Nature Reviews. Cancer, 6, 835–845.

    PubMed  CAS  Google Scholar 

  108. Farace, F., Massard, C., Borghi, E., Bidart, J. M., & Soria, J. C. (2007). Vascular disrupting therapy-induced mobilization of circulating endothelial progenitor cells. Annals of Oncology, 18, 1421–1422.

    PubMed  CAS  Google Scholar 

  109. Ebos, J. M., Lee, C. R., Christensen, J. G., Mutsaers, A. J., & Kerbel, R. S. (2007). Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy. Proceedings of the National Academy of Sciences of the United States of America, 104, 17069–17074.

    PubMed  CAS  Google Scholar 

  110. Brown, A. P., Citrin, D. E., & Camphausen, K. A. (2008). Clinical biomarkers of angiogenesis inhibition. Cancer and Metastasis Reviews, 27, 415–434.

    PubMed  CAS  Google Scholar 

  111. Rini, B. I., Michaelson, M. D., Rosenberg, J. E., Bukowski, R. M., Sosman, J. A., Stadler, W. M., et al. (2008). Antitumor activity and biomarker analysis of sunitinib in patients with bevacizumab-refractory metastatic renal cell carcinoma. Journal of Clinical Oncology, 26, 3743–3748.

    PubMed  CAS  Google Scholar 

  112. Prior, J. O., Montemurro, M., Orcurto, M. V., Michielin, O., Luthi, F., Benhattar, J., et al. (2009). Early prediction of response to sunitinib after imatinib failure by 18F-fluorodeoxyglucose positron emission tomography in patients with gastrointestinal stromal tumor. Journal of Clinical Oncology, 27, 439–445.

    PubMed  CAS  Google Scholar 

  113. Michael, A., Relph, K., & Pandha, H. (2010). Emergence of potential biomarkers of response to anti-angiogenic anti-tumour agents. International Journal of Cancer, 127, 1251–1258.

    CAS  Google Scholar 

  114. Lamuraglia, M., Escudier, B., Chami, L., Schwartz, B., Leclere, J., Roche, A., et al. (2006). To predict progression-free survival and overall survival in metastatic renal cancer treated with sorafenib: Pilot study using dynamic contrast-enhanced Doppler ultrasound. European Journal of Cancer, 42, 2472–2479.

    PubMed  CAS  Google Scholar 

  115. Fournier, L. S., Oudard, S., Thiam, R., Trinquart, L., Banu, E., Medioni, J., et al. (2010). Metastatic renal carcinoma: Evaluation of antiangiogenic therapy with dynamic contrast-enhanced CT. Radiology, 256, 511–518.

    PubMed  Google Scholar 

  116. Thiam, R., Fournier, L. S., Trinquart, L., Medioni, J., Chatellier, G., Balvay, D., et al. (2010). Optimizing the size variation threshold for the CT evaluation of response in metastatic renal cell carcinoma treated with sunitinib. Annals of Oncology, 21, 936–941.

    PubMed  CAS  Google Scholar 

  117. Escudier, B., Pluzanska, A., Koralewski, P., Ravaud, A., Bracarda, S., Szczylik, C., et al. (2007). Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: A randomised, double-blind phase III trial. Lancet, 370, 2103–2111.

    PubMed  Google Scholar 

  118. Rixe, O., Bukowski, R. M., Michaelson, M. D., Wilding, G., Hudes, G. R., Bolte, O., et al. (2007). Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer: A phase II study. The Lancet Oncology, 8, 975–984.

    PubMed  Google Scholar 

  119. Yang, J. C., Haworth, L., Sherry, R. M., Hwu, P., Schwartzentruber, D. J., Topalian, S. L., et al. (2003). A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. The New England Journal of Medicine, 349, 427–434.

    PubMed  CAS  Google Scholar 

  120. Faivre, S., Delbaldo, C., Vera, K., Robert, C., Lozahic, S., Lassau, N., et al. (2006). Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. Journal of Clinical Oncology, 24, 25–35.

    PubMed  CAS  Google Scholar 

  121. van Cruijsen, H., van der Veldt, A. A., Vroling, L., Oosterhoff, D., Broxterman, H. J., Scheper, R. J., et al. (2008). Sunitinib-induced myeloid lineage redistribution in renal cell cancer patients: CD1c+ dendritic cell frequency predicts progression-free survival. Clinical Cancer Research, 14, 5884–5892.

    PubMed  Google Scholar 

  122. George, S., Richmond, A., Elson, P., Jin, T., Wood, L., Garcia, J. A., et al. (2007). WBC changes as a pharmacodynamic marker of outcome in metastatic renal cell carcinoma (mRCC) patients (Pts) receiving sunitinib (p. 5043). Chicago: ASCO.

    Google Scholar 

  123. Griffiths, R. W., Elkord, E., Gilham, D. E., Ramani, V., Clarke, N., Stern, P. L., et al. (2007). Frequency of regulatory T cells in renal cell carcinoma patients and investigation of correlation with survival. Cancer Immunology, Immunotherapy, 56, 1743–1753.

    PubMed  Google Scholar 

  124. Shojaei, F., Wu, X., Malik, A. K., Zhong, C., Baldwin, M. E., Schanz, S., et al. (2007). Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells. Nature Biotechnology, 25, 911–920.

    PubMed  CAS  Google Scholar 

  125. Huang, D., Ding, Y., Zhou, M., Rini, B. I., Petillo, D., Qian, C. N., et al. (2010). Interleukin-8 mediates resistance to antiangiogenic agent sunitinib in renal cell carcinoma. Cancer Research, 70, 1063–1071.

    PubMed  CAS  Google Scholar 

  126. Nikolinakos, P. G., Altorki, N., Yankelevitz, D., Tran, H. T., Yan, S., Rajagopalan, D., et al. (2010). Plasma cytokine and angiogenic factor profiling identifies markers associated with tumor shrinkage in early-stage non-small cell lung cancer patients treated with pazopanib. Cancer Research, 70, 2171–2179.

    PubMed  CAS  Google Scholar 

  127. Hanrahan, E. O., Lin, H. Y., Kim, E. S., Yan, S., Du, D. Z., McKee, K. S., et al. (2010). Distinct patterns of cytokine and angiogenic factor modulation and markers of benefit for vandetanib and/or chemotherapy in patients with non-small-cell lung cancer. Journal of Clinical Oncology, 28, 193–201.

    PubMed  CAS  Google Scholar 

  128. Tartour, E., Mosseri, V., Jouffroy, T., Deneux, L., Jaulerry, C., Brunin, F., et al. (2001). Serum soluble interleukin-2 receptor concentrations as an independent prognostic marker in head and neck cancer. Lancet, 357, 1263–1264.

    PubMed  CAS  Google Scholar 

  129. Tartour, E., Deneux, L., Mosseri, V., Jaulerry, C., Brunin, F., Point, D., et al. (1997). Soluble interleukin-2 receptor serum level as a predictor of locoregional control and survival for patients with head and neck carcinoma: Results of a multivariate prospective study. Cancer, 79, 1401–1408.

    PubMed  CAS  Google Scholar 

  130. Saltz, L. B., Rosen, L. S., Marshall, J. L., Belt, R. J., Hurwitz, H. I., Eckhardt, S. G., et al. (2007). Phase II trial of sunitinib in patients with metastatic colorectal cancer after failure of standard therapy. Journal of Clinical Oncology, 25, 4793–4799.

    PubMed  CAS  Google Scholar 

  131. Bergers, G., & Hanahan, D. (2008). Modes of resistance to anti-angiogenic therapy. Nature Reviews. Cancer, 8, 592–603.

    PubMed  CAS  Google Scholar 

  132. Willett, C. G., Boucher, Y., di Tomaso, E., Duda, D. G., Munn, L. L., Tong, R. T., et al. (2004). Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Natural Medicines, 10, 145–147.

    CAS  Google Scholar 

  133. Hamzah, J., Jugold, M., Kiessling, F., Rigby, P., Manzur, M., Marti, H. H., et al. (2008). Vascular normalization in Rgs5-deficient tumours promotes immune destruction. Nature, 453, 410–414.

    PubMed  CAS  Google Scholar 

  134. Dirkx, A. E., oude Egbrink, M. G., Castermans, K., van der Schaft, D. W., Thijssen, V. L., Dings, R. P., et al. (2006). Anti-angiogenesis therapy can overcome endothelial cell anergy and promote leukocyte-endothelium interactions and infiltration in tumors. FASEB Journal, 20, 621–630.

    PubMed  CAS  Google Scholar 

  135. Li, B., Lalani, A. S., Harding, T. C., Luan, B., Koprivnikar, K., Huan Tu, G., et al. (2006). Vascular endothelial growth factor blockade reduces intratumoral regulatory T cells and enhances the efficacy of a GM-CSF-secreting cancer immunotherapy. Clinical Cancer Research, 12, 6808–6816.

    PubMed  CAS  Google Scholar 

  136. Manning, E. A., Ullman, J. G., Leatherman, J. M., Asquith, J. M., Hansen, T. R., Armstrong, T. D., et al. (2007). A vascular endothelial growth factor receptor-2 inhibitor enhances antitumor immunity through an immune-based mechanism. Clinical Cancer Research, 13, 3951–3959.

    PubMed  CAS  Google Scholar 

  137. Shrimali, R. K., Yu, Z., Theoret, M. R., Chinnasamy, D., Restifo, N. P., & Rosenberg, S. A. (2010). Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer. Cancer Research, 70, 6171–6180.

    PubMed  CAS  Google Scholar 

  138. Nair, S., Boczkowski, D., Moeller, B., Dewhirst, M., Vieweg, J., & Gilboa, E. (2003). Synergy between tumor immunotherapy and antiangiogenic therapy. Blood, 102, 964–971.

    PubMed  CAS  Google Scholar 

  139. Bercovici, N., Haicheur, N., Massicard, S., Vernel-Pauillac, F., Adotevi, O., Landais, D., et al. (2008). Analysis and characterization of antitumor T-cell response after administration of dendritic cells loaded with allogeneic tumor lysate to metastatic melanoma patients. Journal of Immunotherapy, 31, 101–112.

    PubMed  Google Scholar 

  140. Huang, K. W., Wu, H. L., Lin, H. L., Liang, P. C., Chen, P. J., Chen, S. H., et al. (2010). Combining antiangiogenic therapy with immunotherapy exerts better therapeutical effects on large tumors in a woodchuck hepatoma model. Proceedings of the National Academy of Sciences of the United States of America, 107, 14769–14774.

    PubMed  CAS  Google Scholar 

  141. Kerzerho, J., Adotevi, O., Castelli, F. A., Dosset, M., Bernardeau, K., Szely, N., et al. (2010). The angiogenic growth factor and biomarker midkine is a tumor-shared antigen. Journal of Immunology, 185, 418–423.

    CAS  Google Scholar 

  142. Molhoek, K. R., McSkimming, C. C., Olson, W. C., Brautigan, D. L., & Slingluff, C. L., Jr. (2009). Apoptosis of CD4(+)CD25(high) T cells in response to Sirolimus requires activation of T cell receptor and is modulated by IL-2. Cancer Immunology, Immunotherapy, 58, 867–876.

    PubMed  CAS  Google Scholar 

  143. Albini, A., Brigati, C., Ventura, A., Lorusso, G., Pinter, M., Morini, M., et al. (2009). Angiostatin anti-angiogenesis requires IL-12: The innate immune system as a key target. Journal of Translational Medicine, 7, 5.

    PubMed  Google Scholar 

  144. Rini, B. I., Halabi, S., Rosenberg, J. E., Stadler, W. M., Vaena, D. A., Ou, S. S., et al. (2008). Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. Journal of Clinical Oncology, 26, 5422–5428.

    PubMed  CAS  Google Scholar 

  145. Flaherty, K. T. (2010). Where does the combination of sorafenib and interferon in renal cell carcinoma stand? Cancer, 116, 4–7.

    PubMed  CAS  Google Scholar 

  146. Zhao, W., Gu, Y. H., Song, R., Qu, B. Q., & Xu, Q. (2008). Sorafenib inhibits activation of human peripheral blood T cells by targeting LCK phosphorylation. Leukemia, 22, 1226–1233.

    PubMed  CAS  Google Scholar 

  147. Houben, R., Voigt, H., Noelke, C., Hofmeister, V., Becker, J. C., & Schrama, D. (2009). MAPK-independent impairment of T-cell responses by the multikinase inhibitor sorafenib. Molecular Cancer Therapeutics, 8, 433–440.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by Canceropole Ile de France, ANR (Agence Nationale de la Recherche), Ligue contre le Cancer, Association pour la Recherche sur le Cancer, Pole de compétitivité Medicen (Immucan), Centre d’investigation Clinique en Biothérapie (CIC-BT). AP-HP. INSERM, Roche.

Author information

Authors and Affiliations

  1. INSERM U970 PARCC (Paris Cardiovascular Research Center), Universite Paris Descartes, 56 Rue Leblanc, 75015, Paris, France

    Eric Tartour, H. Pere, M. Terme, N. Merillon, J. Taieb, F. Sandoval, F. Quintin-Colonna, K. Lacerda, A. Karadimou, C. Badoual, A. Tedgui & S. Oudard

  2. Service d’Immunologie Biologique, Hôpital Européen Georges Pompidou. Paris. AP-HP, Paris, France

    Eric Tartour & W. H. Fridman

  3. Commissariat à l’Energie Atomique-Saclay, Institut de Biologie et Technologies, Service d’Ingénierie Moléculaire des Protéines, Gif-sur-Yvette, France

    B. Maillere

  4. Unité d’Oncologie Digestive, Service d’Hépatogastroentérologie, Hôpital Européen Georges Pompidou. Paris. AP-HP, Paris, France

    J. Taieb

  5. Ecole Nationale Vétérinaire d’Alfort, 94700, Maisons-Alfort, France

    F. Quintin-Colonna

  6. Service d’Oncologie Médicale, Hôpital Européen Georges Pompidou. Paris. AP-HP, Paris, France

    A. Karadimou & S. Oudard

  7. Service d’Anatomie Pathologie, Hôpital Européen Georges Pompidou. Paris. AP-HP, Paris, France

    C. Badoual

  8. Hôpital Européen Georges Pompidou, Unité d’immunologie biologique, 20 Rue Leblanc, 75015, Paris, France

    Eric Tartour

Authors
  1. Eric Tartour
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H. Pere
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. B. Maillere
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. Terme
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. N. Merillon
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J. Taieb
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. F. Sandoval
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. F. Quintin-Colonna
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. K. Lacerda
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. A. Karadimou
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. C. Badoual
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. A. Tedgui
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. W. H. Fridman
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. S. Oudard
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eric Tartour.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tartour, E., Pere, H., Maillere, B. et al. Angiogenesis and immunity: a bidirectional link potentially relevant for the monitoring of antiangiogenic therapy and the development of novel therapeutic combination with immunotherapy. Cancer Metastasis Rev 30, 83–95 (2011). https://doi.org/10.1007/s10555-011-9281-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-011-9281-4

Keywords

Search

Navigation