Advertisement

Cancer and Metastasis Reviews

, Volume 30, Issue 1, pp 125–140 | Cite as

Improving cancer immunotherapy by targeting tumor-induced immune suppression

  • Trina J. StewartEmail author
  • Mark J. Smyth
Article

Abstract

The status of a host’s immune response influences both the development and progression of a malignancy such that immune responses can have both pro- and anti-tumorigenic effects. Cancer immunotherapy is a form of treatment that aims to improve the ability of a cancer-bearing individual to reject the tumor immunologically. However, antitumor immunity elicited by the host or by immunotherapeutic strategies, can be actively attenuated by mechanisms that limit the strength and/or duration of immune responses, including the presence of immunoregulatory cell types or the production of immunosuppressive factors. As our knowledge of tumor-induced immune suppression increases, it has become obvious that these mechanisms are probably a major barrier to effective therapy. The identification of multiple mechanisms of tumor-induced immune suppression also provides a range of novel targets for new cancer therapies. Given the vital role that a host’s immune response is known to play in cancer progression, therapies that target immune suppressive mechanisms have the potential to enhance anticancer immune responses thus leading to better immune surveillance and the limitation of tumor escape. In this review, mechanisms of tumor-associated immune suppression have been divided into four forms that we have designated as (1) regulatory cells; (2) cytokines/chemokines; (3) T cell tolerance/exhaustion and (4) metabolic. We discuss select mechanisms representing each of these forms of immunosuppression that have been shown to aid tumors in evading host immune surveillance and overview therapeutic strategies that have been recently devised to “suppress these suppressors.”

Keywords

Immune suppression Tumor immunology Immunotherapy MDSC Inhibitory cytokines 

Notes

Acknowledgments

The authors wish to thank their funding partners who include the National Breast Cancer Foundation, Cancer Council of Victoria, The Victorian Breast Cancer Research Consortium, The Susan G. Komen Breast Cancer Foundation, and the National Health and Medical Research Council of Australia.

References

  1. 1.
    Stewart, T. J., Greeneltch, K. M., Lutsiak, M. E., & Abrams, S. I. (2007). Immunological responses can have both pro- and antitumour effects: implications for immunotherapy. Expert Reviews in Molecular Medicine, 9(4), 1–20. doi: 10.1017/S1462399407000233.PubMedGoogle Scholar
  2. 2.
    Hamai, A., Benlalam, H., Meslin, F., Hasmim, M., Carre, T., Akalay, I., et al. Immune surveillance of human cancer: If the cytotoxic t-lymphocytes play the music, does the tumoral system call the tune? Tissue Antigens, 75(1), 1–8, doi: 10.1111/j.1399-0039.2009.01401.x.
  3. 3.
    Knutson, K. L., & Disis, M. L. (2005). Tumor antigen-specific T helper cells in cancer immunity and immunotherapy. Cancer Immunology, Immunotherapy, 54(8), 721–728.PubMedGoogle Scholar
  4. 4.
    Bindea, G., Mlecnik, B., Fridman, W. H., Pages, F., & Galon, J. Natural immunity to cancer in humans. Current Opinion in Immunology, 22(2), 215–222, doi: 10.1016/j.coi.2010.02.006.
  5. 5.
    Dunn, G. P., Old, L. J., & Schreiber, R. D. (2004). The immunobiology of cancer immunosurveillance and immunoediting. Immunity, 21(2), 137–148.PubMedGoogle Scholar
  6. 6.
    Swann, J. B., & Smyth, M. J. (2007). Immune surveillance of tumors. Journal of Clinical Investigation, 117(5), 1137–1146. doi: 10.1172/JCI31405.PubMedGoogle Scholar
  7. 7.
    Ferrone, S., & Whiteside, T. L. (2007). Tumor microenvironment and immune escape. Surgical Oncology Clinics of North America, 16(4), 755–774, viii, doi: 10.1016/j.soc.2007.08.004.Google Scholar
  8. 8.
    Stewart, T. J., & Abrams, S. I. (2008). How tumours escape mass destruction. Oncogene, 27(45), 5894–5903. doi: 10.1038/onc.2008.268.PubMedGoogle Scholar
  9. 9.
    Weiner, L. M., Surana, R., & Wang, S. Monoclonal antibodies: versatile platforms for cancer immunotherapy. Nature Reviews. Immunology, 10(5), 317–327, doi: 10.1038/nri2744.
  10. 10.
    Kapp, M., Rasche, L., Einsele, H., & Grigoleit, G. U. (2009). Cellular therapy to control tumor progression. Current Opinion in Hematology, 16(6), 437–443. doi: 10.1097/MOH.0b013e32832f57d4.PubMedGoogle Scholar
  11. 11.
    Rosenberg, S. A., & Dudley, M. E. (2009). Adoptive cell therapy for the treatment of patients with metastatic melanoma. Current Opinion in Immunology, 21(2), 233–240. doi: 10.1016/j.coi.2009.03.002.PubMedGoogle Scholar
  12. 12.
    Huye, L. E., & Dotti, G. Designing t cells for cancer immunotherapy. Discov Med, 9(47), 297–303.Google Scholar
  13. 13.
    Westwood, J. A., & Kershaw, M. H. Genetic redirection of t cells for cancer therapy. Journal of Leukocyte Biology, 87(5), 791–803, doi: 10.1189/jlb.1209824.
  14. 14.
    Spagnoli, G. C., Ebrahimi, M., Iezzi, G., Mengus, C., & Zajac, P. Contemporary immunotherapy of solid tumors: From tumor-associated antigens to combination treatments. Current Opinion in Drug Discovery & Development, 13(2), 184–192.Google Scholar
  15. 15.
    Romagnani, S., Maggi, E., Liotta, F., Cosmi, L., & Annunziato, F. (2009). Properties and origin of human th17 cells. Molecular Immunology, 47(1), 3–7. doi: 10.1016/j.molimm.2008.12.019.PubMedGoogle Scholar
  16. 16.
    Mougiakakos, D., Choudhury, A., Lladser, A., Kiessling, R., & Johansson, C. C. Regulatory t cells in cancer. Advances in Cancer Research, 107, 57–117, doi: 10.1016/S0065-230X(10)07003-X.
  17. 17.
    Nishikawa, H., & Sakaguchi, S. Regulatory t cells in tumor immunity. International Journal of Cancer, 127(4), 759–767, doi: 10.1002/ijc.25429.
  18. 18.
    Teng, M. W., Ritchie, D. S., Neeson, P., & Smyth, M. J. Biology and clinical observations of regulatory t cells in cancer immunology. Current topics in Microbiology and Immunology, doi: 10.1007/82_2010_50.
  19. 19.
    Serafini, P., Borrello, I., & Bronte, V. (2006). Myeloid suppressor cells in cancer: recruitment, phenotype, properties, and mechanisms of immune suppression. Seminars in Cancer Biology, 16(1), 53–65.PubMedGoogle Scholar
  20. 20.
    Allavena, P., Sica, A., Garlanda, C., & Mantovani, A. (2008). The yin-yang of tumor-associated macrophages in neoplastic progression and immune surveillance. Immunological Reviews, 222, 155–161. doi: 10.1111/j.1600-065X.2008.00607.x.PubMedGoogle Scholar
  21. 21.
    Gabrilovich, D. I., & Nagaraj, S. (2009). Myeloid-derived suppressor cells as regulators of the immune system. Nature Reviews. Immunology, 9(3), 162–174. doi: 10.1038/nri2506.PubMedGoogle Scholar
  22. 22.
    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. doi: 10.1111/j.1600-065X.2008.00602.x.PubMedGoogle Scholar
  23. 23.
    Almand, B., Clark, J. I., Nikitina, E., van Beynen, J., English, N. R., Knight, S. C., et al. (2001). Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. Journal of Immunology, 166(1), 678–689.Google Scholar
  24. 24.
    Diaz-Montero, C. M., Salem, M. L., Nishimura, M. I., Garrett-Mayer, E., Cole, D. J., & Montero, A. J. (2009). Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunology, Immunotherapy, 58(1), 49–59. doi: 10.1007/s00262-008-0523-4.PubMedGoogle Scholar
  25. 25.
    Sica, A., & Bronte, V. (2007). Altered macrophage differentiation and immune dysfunction in tumor development. Journal of Clinical Investigation, 117(5), 1155–1166. doi: 10.1172/JCI31422.PubMedGoogle Scholar
  26. 26.
    Young, M. R., Kolesiak, K., Wright, M. A., & Gabrilovich, D. I. (1999). Chemoattraction of femoral cd34+ progenitor cells by tumor-derived vascular endothelial cell growth factor. Clinical & Experimental Metastasis, 17(10), 881–888.Google Scholar
  27. 27.
    Zea, A. H., Rodriguez, P. C., Atkins, M. B., Hernandez, C., Signoretti, S., Zabaleta, J., et al. (2005). Arginase-producing myeloid suppressor cells in renal cell carcinoma patients: a mechanism of tumor evasion. Cancer Research, 65(8), 3044–3048. doi: 10.1158/0008-5472.CAN-04-4505.PubMedGoogle Scholar
  28. 28.
    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(18), 2546–2553. doi: 10.1200/JCO.2006.08.5829.PubMedGoogle Scholar
  29. 29.
    Hoechst, B., Ormandy, L. A., Ballmaier, M., Lehner, F., Kruger, C., Manns, M. P., et al. (2008). A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces cd4(+)cd25(+)foxp3(+) T cells. Gastroenterology, 135(1), 234–243. doi: 10.1053/j.gastro.2008.03.020.PubMedGoogle Scholar
  30. 30.
    Danna, E. A., Sinha, P., Gilbert, M., Clements, V. K., Pulaski, B. A., & Ostrand-Rosenberg, S. (2004). Surgical removal of primary tumor reverses tumor-induced immunosuppression despite the presence of metastatic disease. Cancer Research, 64(6), 2205–2211.PubMedGoogle Scholar
  31. 31.
    Serafini, P., De Santo, C., Marigo, I., Cingarlini, S., Dolcetti, L., Gallina, G., et al. (2004). Derangement of immune responses by myeloid suppressor cells. Cancer Immunology, Immunotherapy, 53(2), 64–72.PubMedGoogle Scholar
  32. 32.
    de Waal Malefyt, R., Yssel, H., & de Vries, J. E. (1993). Direct effects of il-10 on subsets of human cd4+ t cell clones and resting t cells. Specific inhibition of il-2 production and proliferation. Journal of Immunology, 150(11), 4754–4765.Google Scholar
  33. 33.
    Koch, F., Stanzl, U., Jennewein, P., Janke, K., Heufler, C., Kampgen, E., et al. (1996). High level IL-12 production by murine dendritic cells: upregulation via MHC class II and CD40 molecules and downregulation by IL-4 and IL-10. The Journal of Experimental Medicine, 184(2), 741–746.PubMedGoogle Scholar
  34. 34.
    Moore, K. W., de Waal Malefyt, R., Coffman, R. L., & O’Garra, A. (2001). Interleukin-10 and the interleukin-10 receptor. Annual Review of Immunology, 19, 683–765. doi: 10.1146/annurev.immunol.19.1.683.PubMedGoogle Scholar
  35. 35.
    Bronte, V., Wang, M., Overwijk, W. W., Surman, D. R., Pericle, F., Rosenberg, S. A., et al. (1998). Apoptotic death of CD8+ T lymphocytes after immunization: induction of a suppressive population of Mac-1+/Gr-1+ cells. Journal of Immunology, 161(10), 5313–5320.Google Scholar
  36. 36.
    Gallina, G., Dolcetti, L., Serafini, P., De Santo, C., Marigo, I., Colombo, M. P., et al. (2006). Tumors induce a subset of inflammatory monocytes with immunosuppressive activity on CD8+ T cells. Journal of Clinical Investigation, 116(10), 2777–2790.PubMedGoogle Scholar
  37. 37.
    Zea, A. H., Rodriguez, P. C., Culotta, K. S., Hernandez, C. P., DeSalvo, J., Ochoa, J. B., et al. (2004). l-Arginine modulates CD3zeta expression and T cell function in activated human T lymphocytes. Cellular Immunology, 232(1–2), 21–31.PubMedGoogle Scholar
  38. 38.
    De Santo, C., Serafini, P., Marigo, I., Dolcetti, L., Bolla, M., Del Soldato, P., et al. (2005). Nitroaspirin corrects immune dysfunction in tumor-bearing hosts and promotes tumor eradication by cancer vaccination. Proceedings of the National Academy of Sciences of the United States of America, 102(11), 4185–4190.PubMedGoogle Scholar
  39. 39.
    Pekarek, L. A., Starr, B. A., Toledano, A. Y., & Schreiber, H. (1995). Inhibition of tumor growth by elimination of granulocytes. The Journal of Experimental Medicine, 181(1), 435–440.PubMedGoogle Scholar
  40. 40.
    Stewart, T. J., Liewehr, D. J., Steinberg, S. M., Greeneltch, K. M., & Abrams, S. I. (2009). Modulating the expression of IFN regulatory factor 8 alters the protumorigenic behavior of CD11b+Gr-1+ myeloid cells. Journal of Immunology, 183(1), 117–128. doi: 10.4049/jimmunol.0804132.Google Scholar
  41. 41.
    Stewart, T. J., Greeneltch, K. M., Reid, J. E., Liewehr, D. J., Steinberg, S. M., Liu, K., et al. (2009). Interferon regulatory factor-8 modulates the development of tumour-induced CD11B+Gr-1+ myeloid cells. Journal of Cellular and Molecular Medicine, 13(9B), 3939–3950. doi: 10.1111/j.1582-4934.2009.00685.x.PubMedGoogle Scholar
  42. 42.
    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(12), 1314–1321. doi: 10.1038/nm1325.Google Scholar
  43. 43.
    Nefedova, Y., Nagaraj, S., Rosenbauer, A., Muro-Cacho, C., Sebti, S. M., & Gabrilovich, D. I. (2005). 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 Research, 65(20), 9525–9535.PubMedGoogle Scholar
  44. 44.
    Sinha, P., Clements, V. K., & Ostrand-Rosenberg, S. (2005). Reduction of myeloid-derived suppressor cells and induction of m1 macrophages facilitate the rejection of established metastatic disease. Journal of Immunology, 174(2), 636–645.Google Scholar
  45. 45.
    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(15), 4441–4449.PubMedGoogle Scholar
  46. 46.
    Young, M. R., Lozano, Y., Ihm, J., Wright, M. A., & Prechel, M. M. (1996). Vitamin D3 treatment of tumor bearers can stimulate immune competence and reduce tumor growth when treatment coincides with a heightened presence of natural suppressor cells. Cancer Letters, 104(2), 153–161.PubMedGoogle Scholar
  47. 47.
    Young, M. R., & Wright, M. A. (1992). Myelopoiesis-associated immune suppressor cells in mice bearing metastatic Lewis lung carcinoma tumors: gamma interferon plus tumor necrosis factor alpha synergistically reduces immune suppressor and tumor growth-promoting activities of bone marrow cells and diminishes tumor recurrence and metastasis. Cancer Research, 52(22), 6335–6340.PubMedGoogle Scholar
  48. 48.
    Mirza, N., Fishman, M., Fricke, I., Dunn, M., Neuger, A. M., Frost, T. J., et al. (2006). All-trans-retinoic acid improves differentiation of myeloid cells and immune response in cancer patients. Cancer Research, 66(18), 9299–9307. doi: 10.1158/0008-5472.CAN-06-1690.PubMedGoogle Scholar
  49. 49.
    Ko, J. S., Rayman, P., Ireland, J., Swaidani, S., Li, G., Bunting, K. D., et al. Direct and differential suppression of myeloid-derived suppressor cell subsets by sunitinib is compartmentally constrained. Cancer Research, 70(9), 3526–3536, doi: 10.1158/0008-5472.CAN-09-3278.
  50. 50.
    Le, H. K., Graham, L., Cha, E., Morales, J. K., Manjili, M. H., & Bear, H. D. (2009). Gemcitabine directly inhibits myeloid derived suppressor cells in BALB/c mice bearing 4T1 mammary carcinoma and augments expansion of T cells from tumor-bearing mice. International Immunopharmacology, 9(7–8), 900–909. doi: 10.1016/j.intimp.2009.03.015.PubMedGoogle Scholar
  51. 51.
    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(6), 2514–2522. doi: 10.1158/0008-5472.CAN-08-4709.PubMedGoogle Scholar
  52. 52.
    Suzuki, E., Kapoor, V., Jassar, A. S., Kaiser, L. R., & Albelda, S. M. (2005). Gemcitabine selectively eliminates splenic Gr-1+/CD11b+myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clinical Cancer Research, 11(18), 6713–6721.PubMedGoogle Scholar
  53. 53.
    Vincent, J., Mignot, G., Chalmin, F., Ladoire, S., Bruchard, M., Chevriaux, A., et al. 5-fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced t cell-dependent antitumor immunity. Cancer Research, 70(8), 3052–3061, doi: 10.1158/0008-5472.CAN-09-3690.
  54. 54.
    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(6), 2148–2157. doi: 10.1158/1078-0432.CCR-08-1332.PubMedGoogle Scholar
  55. 55.
    Fridlender, Z. G., Sun, J., Singhal, S., Kapoor, V., Cheng, G., Suzuki, E., et al. Chemotherapy delivered after viral immunogene therapy augments antitumor efficacy via multiple immune-mediated mechanisms. Molecular Therapy, doi: 10.1038/mt.2010.159.
  56. 56.
    Godfrey, D. I., Hammond, K. J., Poulton, L. D., Smyth, M. J., & Baxter, A. G. (2000). NKT cells: facts, functions and fallacies. Immunology Today, 21(11), 573–583.PubMedGoogle Scholar
  57. 57.
    Godfrey, D. I., Stankovic, S., & Baxter, A. G. (2010). Raising the NKT cell family. Nature Immunology, 11(3), 197–206. doi: 10.1038/ni.1841.PubMedGoogle Scholar
  58. 58.
    Smyth, M. J., Crowe, N. Y., Hayakawa, Y., Takeda, K., Yagita, H., & Godfrey, D. I. (2002). NKT cells—conductors of tumor immunity? Current Opinion in Immunology, 14(2), 165–171.PubMedGoogle Scholar
  59. 59.
    Smyth, M. J., & Godfrey, D. I. (2000). NKT cells and tumor immunity—a double-edged sword. Nature Immunology, 1(6), 459–460. doi: 10.1038/82698.PubMedGoogle Scholar
  60. 60.
    Cerundolo, V., Silk, J. D., Masri, S. H., & Salio, M. (2009). Harnessing invariant NKT cells in vaccination strategies. Nature Reviews. Immunology, 9(1), 28–38. doi: 10.1038/nri2451.PubMedGoogle Scholar
  61. 61.
    Smyth, M. J., Crowe, N. Y., Pellicci, D. G., Kyparissoudis, K., Kelly, J. M., Takeda, K., et al. (2002). Sequential production of interferon-gamma by nk1.1(+) t cells and natural killer cells is essential for the antimetastatic effect of alpha-galactosylceramide. Blood, 99(4), 1259–1266.Google Scholar
  62. 62.
    Ambrosino, E., Terabe, M., Halder, R. C., Peng, J., Takaku, S., Miyake, S., et al. (2007). Cross-regulation between type I and type II nkt cells in regulating tumor immunity: a new immunoregulatory axis. Journal of Immunology, 179(8), 5126–5136.Google Scholar
  63. 63.
    Moodycliffe, A. M., Nghiem, D., Clydesdale, G., & Ullrich, S. E. (2000). Immune suppression and skin cancer development: regulation by NKT cells. Nature Immunology, 1(6), 521–525. doi: 10.1038/82782.PubMedGoogle Scholar
  64. 64.
    Terabe, M., Khanna, C., Bose, S., Melchionda, F., Mendoza, A., Mackall, C. L., et al. (2006). Cd1d-restricted natural killer t cells can down-regulate tumor immunosurveillance independent of interleukin-4 receptor-signal transducer and activator of transcription 6 or transforming growth factor-beta. Cancer Research, 66(7), 3869–3875.PubMedGoogle Scholar
  65. 65.
    Terabe, M., Matsui, S., Noben-Trauth, N., Chen, H., Watson, C., Donaldson, D. D., et al. (2000). NKT cell-mediated repression of tumor immunosurveillance by IL-13 and the IL-4R-STAT6 pathway. Nature Immunology, 1(6), 515–520.PubMedGoogle Scholar
  66. 66.
    Terabe, M., Swann, J., Ambrosino, E., Sinha, P., Takaku, S., Hayakawa, Y., et al. (2005). A nonclassical non-Valpha14Jalpha18 CD1d-restricted (type II) NKT cell is sufficient for down-regulation of tumor immunosurveillance. The Journal of Experimental Medicine, 202(12), 1627–1633.PubMedGoogle Scholar
  67. 67.
    Park, J. M., Terabe, M., Donaldson, D. D., Forni, G., & Berzofsky, J. A. (2008). Natural immunosurveillance against spontaneous, autochthonous breast cancers revealed and enhanced by blockade of IL-13-mediated negative regulation. Cancer Immunology, Immunotherapy, 57(6), 907–912. doi: 10.1007/s00262-007-0414-0.PubMedGoogle Scholar
  68. 68.
    Terabe, M., Matsui, S., Park, J. M., Mamura, M., Noben-Trauth, N., Donaldson, D. D., et al. (2003). Transforming growth factor-beta production and myeloid cells are an effector mechanism through which CD1d-restricted t cells block cytotoxic T lymphocyte-mediated tumor immunosurveillance: abrogation prevents tumor recurrence. The Journal of Experimental Medicine, 198(11), 1741–1752.PubMedGoogle Scholar
  69. 69.
    Terabe, M., Park, J. M., & Berzofsky, J. A. (2004). Role of IL-13 in regulation of anti-tumor immunity and tumor growth. Cancer Immunology, Immunotherapy, 53(2), 79–85.PubMedGoogle Scholar
  70. 70.
    Parmiani, G., Rivoltini, L., Andreola, G., & Carrabba, M. (2000). Cytokines in cancer therapy. Immunology Letters, 74(1), 41–44.PubMedGoogle Scholar
  71. 71.
    Stewart, T. J., & Smyth, M. J. (2009). Chemokine–chemokine receptors in cancer immunotherapy. Immunotherapy, 1(1), 109–127. doi: 10.2217/1750743X.1.1.109.PubMedGoogle Scholar
  72. 72.
    Gorelik, L., & Flavell, R. A. (2002). Transforming growth factor-beta in T-cell biology. Nature Reviews. Immunology, 2(1), 46–53. doi: 10.1038/nri704.PubMedGoogle Scholar
  73. 73.
    Letterio, J. J., & Roberts, A. B. (1998). Regulation of immune responses by TGF-beta. Annual Review of Immunology, 16, 137–161. doi: 10.1146/annurev.immunol.16.1.137.PubMedGoogle Scholar
  74. 74.
    Li, M. O., & Flavell, R. A. (2008). TGF-beta: a master of all T cell trades. Cell, 134(3), 392–404. doi: 10.1016/j.cell.2008.07.025.PubMedGoogle Scholar
  75. 75.
    Borkowski, T. A., Letterio, J. J., Farr, A. G., & Udey, M. C. (1996). A role for endogenous transforming growth factor beta 1 in langerhans cell biology: the skin of transforming growth factor beta 1 null mice is devoid of epidermal langerhans cells. The Journal of Experimental Medicine, 184(6), 2417–2422.PubMedGoogle Scholar
  76. 76.
    Geissmann, F., Revy, P., Regnault, A., Lepelletier, Y., Dy, M., Brousse, N., et al. (1999). TGF-beta 1 prevents the noncognate maturation of human dendritic langerhans cells. Journal of Immunology, 162(8), 4567–4575.Google Scholar
  77. 77.
    Bierie, B., & Moses, H. L. (2006). Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer. Nature Reviews. Cancer, 6(7), 506–520. doi: 10.1038/nrc1926.PubMedGoogle Scholar
  78. 78.
    Takaku, S., Terabe, M., Ambrosino, E., Peng, J., Lonning, S., McPherson, J. M., et al. Blockade of tgf-beta enhances tumor vaccine efficacy mediated by cd8(+) t cells. International Journal of Cancer, 126(7), 1666–1674, doi: 10.1002/ijc.24961.
  79. 79.
    Terabe, M., Ambrosino, E., Takaku, S., O’Konek, J. J., Venzon, D., Lonning, S., et al. (2009). Synergistic enhancement of CD8+ T cell-mediated tumor vaccine efficacy by an anti-transforming growth factor-beta monoclonal antibody. Clinical Cancer Research, 15(21), 6560–6569. doi: 10.1158/1078-0432.CCR-09-1066.PubMedGoogle Scholar
  80. 80.
    Ueda, R., Fujita, M., Zhu, X., Sasaki, K., Kastenhuber, E. R., Kohanbash, G., et al. (2009). Systemic inhibition of transforming growth factor-beta in glioma-bearing mice improves the therapeutic efficacy of glioma-associated antigen peptide vaccines. Clinical Cancer Research, 15(21), 6551–6559. doi: 10.1158/1078-0432.CCR-09-1067.PubMedGoogle Scholar
  81. 81.
    Nagaraj, N. S., & Datta, P. K. Targeting the transforming growth factor-beta signaling pathway in human cancer. Expert Opinion on Investigational Drugs, 19(1), 77-91, doi: 10.1517/13543780903382609.
  82. 82.
    Uhl, M., Aulwurm, S., Wischhusen, J., Weiler, M., Ma, J. Y., Almirez, R., et al. (2004). SD-208, a novel transforming growth factor beta receptor I kinase inhibitor, inhibits growth and invasiveness and enhances immunogenicity of murine and human glioma cells in vitro and in vivo. Cancer Research, 64(21), 7954–7961. doi: 10.1158/0008-5472.CAN-04-1013.PubMedGoogle Scholar
  83. 83.
    Hau, P., Jachimczak, P., & Bogdahn, U. (2009). Treatment of malignant gliomas with TGF-beta2 antisense oligonucleotides. Expert Review of Anticancer Therapy, 9(11), 1663–1674. doi: 10.1586/era.09.138.PubMedGoogle Scholar
  84. 84.
    Hau, P., Jachimczak, P., Schlingensiepen, R., Schulmeyer, F., Jauch, T., Steinbrecher, A., et al. (2007). Inhibition of TGF-beta2 with AP 12009 in recurrent malignant gliomas: from preclinical to phase I/II studies. Oligonucleotides, 17(2), 201–212. doi: 10.1089/oli.2006.0053.PubMedGoogle Scholar
  85. 85.
    Nemunaitis, J., Nemunaitis, M., Senzer, N., Snitz, P., Bedell, C., Kumar, P., et al. (2009). Phase II trial of Belagenpumatucel-l, a TGF-beta2 antisense gene modified allogeneic tumor vaccine in advanced non small cell lung cancer (NSCLC) patients. Cancer Gene Therapy, 16(8), 620–624. doi: 10.1038/cgt.2009.15.PubMedGoogle Scholar
  86. 86.
    Vicari, A. P., & Trinchieri, G. (2004). Interleukin-10 in viral diseases and cancer: exiting the labyrinth? Immunological Reviews, 202, 223–236. doi: 10.1111/j.0105-2896.2004.00216.x.PubMedGoogle Scholar
  87. 87.
    Bagri, A., Kouros-Mehr, H., Leong, K. G., & Plowman, G. D. Use of anti-vegf adjuvant therapy in cancer: Challenges and rationale. Trends in Molecular Medicine, 16(3), 122–132, doi: 10.1016/j.molmed.2010.01.004.
  88. 88.
    Johnson, B., Osada, T., Clay, T., Lyerly, H., & Morse, M. (2009). Physiology and therapeutics of vascular endothelial growth factor in tumor immunosuppression. Current Molecular Medicine, 9(6), 702–707.PubMedGoogle Scholar
  89. 89.
    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(10), 2963–2970.PubMedGoogle Scholar
  90. 90.
    Alfaro, C., Suarez, N., Gonzalez, A., Solano, S., Erro, L., Dubrot, J., et al. (2009). Influence of bevacizumab, sunitinib and sorafenib as single agents or in combination on the inhibitory effects of VEGF on human dendritic cell differentiation from monocytes. British Journal of Cancer, 100(7), 1111–1119. doi: 10.1038/sj.bjc.6604965.PubMedGoogle Scholar
  91. 91.
    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(22), 6808–6816. doi: 10.1158/1078-0432.CCR-06-1558.PubMedGoogle Scholar
  92. 92.
    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(8), 1115–1124. doi: 10.1007/s00262-007-0441-x.PubMedGoogle Scholar
  93. 93.
    Rini, B. I., Weinberg, V., Fong, L., Conry, S., Hershberg, R. M., & Small, E. J. (2006). Combination immunotherapy with prostatic acid phosphatase pulsed antigen-presenting cells (provenge) plus bevacizumab in patients with serologic progression of prostate cancer after definitive local therapy. Cancer, 107(1), 67–74. doi: 10.1002/cncr.21956.PubMedGoogle Scholar
  94. 94.
    Conti, I., & Rollins, B. J. (2004). CCL2 (monocyte chemoattractant protein-1) and cancer. Seminars in Cancer Biology, 14(3), 149–154.PubMedGoogle Scholar
  95. 95.
    Hasegawa, H., Inoue, A., Muraoka, M., Yamanouchi, J., Miyazaki, T., & Yasukawa, M. (2007). Therapy for pneumonitis and sialadenitis by accumulation of CCR2-expressing CD4+CD25+ regulatory T cells in MRL/lpr mice. Arthritis Research & Therapy, 9(1), R15. doi: 10.1186/ar2122.Google Scholar
  96. 96.
    Hu, K., Xiong, J., Ji, K., Sun, H., Wang, J., & Liu, H. (2007). Recombined CC chemokine ligand 2 into B16 cells induces production of th2-dominant [correction of dominanted] cytokines and inhibits melanoma metastasis. Immunology Letters, 113(1), 19–28. doi: 10.1016/j.imlet.2007.07.004.PubMedGoogle Scholar
  97. 97.
    Peng, L., Shu, S., & Krauss, J. C. (1997). Monocyte chemoattractant protein inhibits the generation of tumor-reactive t cells. Cancer Research, 57(21), 4849–4854.PubMedGoogle Scholar
  98. 98.
    Ueno, T., Toi, M., Saji, H., Muta, M., Bando, H., Kuroi, K., et al. (2000). Significance of macrophage chemoattractant protein-1 in macrophage recruitment, angiogenesis, and survival in human breast cancer. Clinical Cancer Research, 6(8), 3282–3289.PubMedGoogle Scholar
  99. 99.
    Jordan, J. T., Sun, W., Hussain, S. F., DeAngulo, G., Prabhu, S. S., & Heimberger, A. B. (2008). Preferential migration of regulatory T cells mediated by glioma-secreted chemokines can be blocked with chemotherapy. Cancer Immunology, Immunotherapy, 57(1), 123–131. doi: 10.1007/s00262-007-0336-x.PubMedGoogle Scholar
  100. 100.
    Pollard, J. W. (2004). Tumour-educated macrophages promote tumour progression and metastasis. Nature Reviews. Cancer, 4(1), 71–78. doi: 10.1038/nrc1256nrc1256.PubMedGoogle Scholar
  101. 101.
    Loberg, R. D., Ying, C., Craig, M., Day, L. L., Sargent, E., Neeley, C., et al. (2007). Targeting CCL2 with systemic delivery of neutralizing antibodies induces prostate cancer tumor regression in vivo. Cancer Research, 67(19), 9417–9424.PubMedGoogle Scholar
  102. 102.
    Loberg, R. D., Ying, C., Craig, M., Yan, L., Snyder, L. A., & Pienta, K. J. (2007). CCL2 as an important mediator of prostate cancer growth in vivo through the regulation of macrophage infiltration. Neoplasia, 9(7), 556–562.PubMedGoogle Scholar
  103. 103.
    Fridlender, Z. G., Buchlis, G., Kapoor, V., Cheng, G., Sun, J., Singhal, S., et al. Ccl2 blockade augments cancer immunotherapy. Cancer Research, 70(1), 109–118, doi: 10.1158/0008-5472.CAN-09-2326.
  104. 104.
    Li, J. H., Rosen, D., Sondel, P., & Berke, G. (2002). Immune privilege and FasL: two ways to inactivate effector cytotoxic t lymphocytes by FasL-expressing cells. Immunology, 105(3), 267–277.PubMedGoogle Scholar
  105. 105.
    Schwartz, R. H. (2003). T cell anergy. Annual Review of Immunology, 21, 305–334. doi: 10.1146/annurev.immunol.21.120601.141110.PubMedGoogle Scholar
  106. 106.
    Greiner, J. W., Zeytin, H., Anver, M. R., & Schlom, J. (2002). Vaccine-based therapy directed against carcinoembryonic antigen demonstrates antitumor activity on spontaneous intestinal tumors in the absence of autoimmunity. Cancer Research, 62(23), 6944–6951.PubMedGoogle Scholar
  107. 107.
    Eder, J. P., Kantoff, P. W., Roper, K., Xu, G. X., Bubley, G. J., Boyden, J., et al. (2000). A phase I trial of a recombinant vaccinia virus expressing prostate-specific antigen in advanced prostate cancer. Clinical Cancer Research, 6(5), 1632–1638.PubMedGoogle Scholar
  108. 108.
    Marshall, J. L., Gulley, J. L., Arlen, P. M., Beetham, P. K., Tsang, K. Y., Slack, R., et al. (2005). Phase i study of sequential vaccinations with fowlpox-CEA(6D)-TRICOM alone and sequentially with vaccinia-CEA(6D)-TRICOM, with and without granulocyte-macrophage colony-stimulating factor, in patients with carcinoembryonic antigen-expressing carcinomas. Journal of Clinical Oncology, 23(4), 720–731. doi: 10.1200/JCO.2005.10.206.PubMedGoogle Scholar
  109. 109.
    Frey, A. B., & Monu, N. (2008). Signaling defects in anti-tumor T cells. Immunological Reviews, 222, 192–205. doi: 10.1111/j.1600-065X.2008.00606.x.PubMedGoogle Scholar
  110. 110.
    Whiteside, T. L. Immune responses to malignancies. Journal of Allergy and Clinical Immunology, 125(2 Suppl 2), S272–S283, doi: 10.1016/j.jaci.2009.09.045.
  111. 111.
    Egen, J. G., Kuhns, M. S., & Allison, J. P. (2002). CTLA-4: new insights into its biological function and use in tumor immunotherapy. Nature Immunology, 3(7), 611–618.PubMedGoogle Scholar
  112. 112.
    Boasso, A., Herbeuval, J. P., Hardy, A. W., Winkler, C., & Shearer, G. M. (2005). Regulation of indoleamine 2, 3-dioxygenase and tryptophanyl-tRNA-synthetase by CTLA-4-Fc in human CD4+ T cells. Blood, 105(4), 1574–1581. doi: 10.1182/blood-2004-06-2089.PubMedGoogle Scholar
  113. 113.
    Mangsbo, S. M., Sandin, L. C., Anger, K., Korman, A. J., Loskog, A., & Totterman, T. H. Enhanced tumor eradication by combining ctla-4 or pd-1 blockade with cpg therapy. Journal of Immunotherapy, 33(3), 225–235, doi: 10.1097/CJI.0b013e3181c01fcb.
  114. 114.
    Takeda, K., Kojima, Y., Uno, T., Hayakawa, Y., Teng, M. W., Yoshizawa, H., et al. Combination therapy of established tumors by antibodies targeting immune activating and suppressing molecules. Journal of Immunology, 184(10), 5493–5501, doi: 10.4049/jimmunol.0903033.
  115. 115.
    Sarnaik, A. A., & Weber, J. S. (2009). Recent advances using anti-CTLA-4 for the treatment of melanoma. Cancer Journal, 15(3), 169–173. doi: 10.1097/PPO.0b013e3181a7450f.Google Scholar
  116. 116.
    Agarwala, S. S. Novel immunotherapies as potential therapeutic partners for traditional or targeted agents: Cytotoxic t-lymphocyte antigen-4 blockade in advanced melanoma. Melanoma Research, 20(1), 1–10, doi: 10.1097/CMR.0b013e328333bbc8.
  117. 117.
    Page, D. B., Yuan, J., & Wolchok, J. D. Targeting cytotoxic t-lymphocyte antigen 4 in immunotherapies for melanoma and other cancers. Immunotherapy, 2(3), 367–379, doi: 10.2217/imt.10.21.
  118. 118.
    Weber, J. S. (2006). The clinical utility of cytotoxic T lymphocyte antigen 4 abrogation by human antibodies. Melanoma Research, 16(5), 379–383. doi: 10.1097/01.cmr.0000232292.06785.a3.PubMedGoogle Scholar
  119. 119.
    Dong, H., Strome, S. E., Salomao, D. R., Tamura, H., Hirano, F., Flies, D. B., et al. (2002). Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Natural Medicines, 8(8), 793–800.Google Scholar
  120. 120.
    Fourcade, J., Kudela, P., Sun, Z., Shen, H., Land, S. R., Lenzner, D., et al. (2009). PD-1 is a regulator of NY-ESO-1-specific CD8+ T cell expansion in melanoma patients. Journal of Immunology, 182(9), 5240–5249. doi: 10.4049/jimmunol.0803245.Google Scholar
  121. 121.
    Matsuzaki, J., Gnjatic, S., Mhawech-Fauceglia, P., Beck, A., Miller, A., Tsuji, T., et al. Tumor-infiltrating ny-eso-1-specific cd8+ t cells are negatively regulated by lag-3 and pd-1 in human ovarian cancer. Proceedings of the National Academy of Sciences of the United States of America, 107(17), 7875–7880, doi: 10.1073/pnas.1003345107.
  122. 122.
    Fourcade, J., Sun, Z., Benallaoua, M., Guillaume, P., Luescher, I. F., Sander, C., et al. Upregulation of tim-3 and pd-1 expression is associated with tumor antigen-specific cd8+ t cell dysfunction in melanoma patients. Journal of Experimental Medicine, doi: 10.1084/jem.20100637.
  123. 123.
    Ichikawa, M., & Chen, L. (2005). Role of B7-H1 and B7-H4 molecules in down-regulating effector phase of T-cell immunity: novel cancer escaping mechanisms. Frontiers in Bioscience, 10, 2856–2860.PubMedGoogle Scholar
  124. 124.
    Wang, W., Lau, R., Yu, D., Zhu, W., Korman, A., & Weber, J. (2009). PD1 blockade reverses the suppression of melanoma antigen-specific CTL by CD4+ CD25(hi) regulatory t cells. International Immunology, 21(9), 1065–1077. doi: 10.1093/intimm/dxp072.PubMedGoogle Scholar
  125. 125.
    Curiel, T. J., Wei, S., Dong, H., Alvarez, X., Cheng, P., Mottram, P., et al. (2003). Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Natural Medicines, 9(5), 562–567. doi: 10.1038/nm863.Google Scholar
  126. 126.
    Brahmer, J. R., Drake, C. G., Wollner, I., Powderly, J. D., Picus, J., Sharfman, W. H., et al. Phase i study of single-agent anti-programmed death-1 (mdx-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. Journal of Clinical Oncology, 28(19), 3167–3175, doi: 10.1200/JCO.2009.26.7609.
  127. 127.
    Li, P., Yin, Y. L., Li, D., Kim, S. W., & Wu, G. (2007). Amino acids and immune function. The British Journal of Nutrition, 98(2), 237–252. doi: 10.1017/S000711450769936X.PubMedGoogle Scholar
  128. 128.
    Bronte, V., & Zanovello, P. (2005). Regulation of immune responses by l-arginine metabolism. Nature Reviews. Immunology, 5(8), 641–654.PubMedGoogle Scholar
  129. 129.
    Mocellin, S., Bronte, V., & Nitti, D. (2007). Nitric oxide, a double edged sword in cancer biology: searching for therapeutic opportunities. Medicinal Research Reviews, 27(3), 317–352. doi: 10.1002/med.20092.PubMedGoogle Scholar
  130. 130.
    Rodriguez, P. C., Quiceno, D. G., Zabaleta, J., Ortiz, B., Zea, A. H., Piazuelo, M. B., et al. (2004). Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer Research, 64(16), 5839–5849.PubMedGoogle Scholar
  131. 131.
    Bronte, V., Kasic, T., Gri, G., Gallana, K., Borsellino, G., Marigo, I., et al. (2005). Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers. The Journal of Experimental Medicine, 201(8), 1257–1268.PubMedGoogle Scholar
  132. 132.
    Stagg, J., & Smyth, M. J. Extracellular adenosine triphosphate and adenosine in cancer. Oncogene, doi: 10.1038/onc.2010.292.
  133. 133.
    Mandapathil, M., Hilldorfer, B., Szczepanski, M. J., Czystowska, M., Szajnik, M., Ren, J., et al. Generation and accumulation of immunosuppressive adenosine by human cd4+cd25highfoxp3+ regulatory t cells. Journal of Biological Chemistry, 285(10), 7176–7186, doi: 10.1074/jbc.M109.047423.
  134. 134.
    Jin, D., Fan, J., Wang, L., Thompson, L. F., Liu, A., Daniel, B. J., et al. Cd73 on tumor cells impairs antitumor t-cell responses: A novel mechanism of tumor-induced immune suppression. Cancer Research, 70(6), 2245–2255, doi: 10.1158/0008-5472.CAN-09-3109.
  135. 135.
    Takedachi, M., Qu, D., Ebisuno, Y., Oohara, H., Joachims, M. L., McGee, S. T., et al. (2008). CD73-generated adenosine restricts lymphocyte migration into draining lymph nodes. Journal of Immunology, 180(9), 6288–6296.Google Scholar
  136. 136.
    Stagg, J., Divisekera, U., McLaughlin, N., Sharkey, J., Pommey, S., Denoyer, D., et al. Anti-cd73 antibody therapy inhibits breast tumor growth and metastasis. Proceedings of the National Academy of Sciences of the United States of America, 107(4), 1547–1552, doi: 10.1073/pnas.0908801107.
  137. 137.
    Uyttenhove, C., Pilotte, L., Theate, I., Stroobant, V., Colau, D., Parmentier, N., et al. (2003). Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2, 3-dioxygenase. Natural Medicines, 9(10), 1269–1274. doi: 10.1038/nm934nm934.Google Scholar
  138. 138.
    Liu, X., Newton, R. C., Friedman, S. M., & Scherle, P. A. (2009). Indoleamine 2, 3-dioxygenase, an emerging target for anti-cancer therapy. Current Cancer Drug Targets, 9(8), 938–952.PubMedGoogle Scholar
  139. 139.
    Lob, S., Konigsrainer, A., Rammensee, H. G., Opelz, G., & Terness, P. (2009). Inhibitors of indoleamine-2, 3-dioxygenase for cancer therapy: can we see the wood for the trees? Nature Reviews. Cancer, 9(6), 445–452. doi: 10.1038/nrc2639.PubMedGoogle Scholar
  140. 140.
    Munn, D. H., Zhou, M., Attwood, J. T., Bondarev, I., Conway, S. J., Marshall, B., et al. (1998). Prevention of allogeneic fetal rejection by tryptophan catabolism. Science, 281(5380), 1191–1193.PubMedGoogle Scholar
  141. 141.
    Grohmann, U., Orabona, C., Fallarino, F., Vacca, C., Calcinaro, F., Falorni, A., et al. (2002). CTLA-4-Ig regulates tryptophan catabolism in vivo. Nature Immunology, 3(11), 1097–1101. doi: 10.1038/ni846ni846.PubMedGoogle Scholar
  142. 142.
    Munn, D. H., Sharma, M. D., Hou, D., Baban, B., Lee, J. R., Antonia, S. J., et al. (2004). Expression of indoleamine 2, 3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes. Journal of Clinical Investigation, 114(2), 280–290. doi: 10.1172/JCI21583.PubMedGoogle Scholar
  143. 143.
    Munn, D. H., & Mellor, A. L. (2007). Indoleamine 2, 3-dioxygenase and tumor-induced tolerance. Journal of Clinical Investigation, 117(5), 1147–1154. doi: 10.1172/JCI31178.PubMedGoogle Scholar
  144. 144.
    Muller, A. J., & Prendergast, G. C. (2007). Indoleamine 2, 3-dioxygenase in immune suppression and cancer. Current Cancer Drug Targets, 7(1), 31–40.PubMedGoogle Scholar
  145. 145.
    Muller, A. J., DuHadaway, J. B., Donover, P. S., Sutanto-Ward, E., & Prendergast, G. C. (2005). Inhibition of indoleamine 2, 3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Natural Medicines, 11(3), 312–319. doi: 10.1038/nm1196.Google Scholar
  146. 146.
    Wang, M. T., Honn, K. V., & Nie, D. (2007). Cyclooxygenases, prostanoids, and tumor progression. Cancer and Metastasis Reviews, 26(3–4), 525–534. doi: 10.1007/s10555-007-9096-5.PubMedGoogle Scholar
  147. 147.
    Gasparini, G., Longo, R., Sarmiento, R., & Morabito, A. (2003). Inhibitors of cyclo-oxygenase 2: a new class of anticancer agents? The Lancet Oncology, 4(10), 605–615.PubMedGoogle Scholar
  148. 148.
    Sarkar, F. H., Adsule, S., Li, Y., & Padhye, S. (2007). Back to the future: COX-2 inhibitors for chemoprevention and cancer therapy. Mini Rev Med Chem, 7(6), 599–608.PubMedGoogle Scholar
  149. 149.
    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(3), 377–386. doi: 10.1093/carcin/bgp014.PubMedGoogle Scholar
  150. 150.
    Harris, S. G., Padilla, J., Koumas, L., Ray, D., & Phipps, R. P. (2002). Prostaglandins as modulators of immunity. Trends in Immunology, 23(3), 144–150.PubMedGoogle Scholar
  151. 151.
    Pockaj, B. A., Basu, G. D., Pathangey, L. B., Gray, R. J., Hernandez, J. L., Gendler, S. J., et al. (2004). Reduced T-cell and dendritic cell function is related to cyclooxygenase-2 overexpression and prostaglandin E2 secretion in patients with breast cancer. Annals of Surgical Oncology, 11(3), 328–339.PubMedGoogle Scholar
  152. 152.
    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(12), 5211–5220. doi: 10.1158/0008-5472.CAN-05-0141.PubMedGoogle Scholar
  153. 153.
    Stolina, M., Sharma, S., Lin, Y., Dohadwala, M., Gardner, B., Luo, J., et al. (2000). Specific inhibition of cyclooxygenase 2 restores antitumor reactivity by altering the balance of IL-10 and IL-12 synthesis. Journal of Immunology, 164(1), 361–370.Google Scholar
  154. 154.
    Basu, G. D., Tinder, T. L., Bradley, J. M., Tu, T., Hattrup, C. L., Pockaj, B. A., et al. (2006). Cyclooxygenase-2 inhibitor enhances the efficacy of a breast cancer vaccine: role of IDO. Journal of Immunology, 177(4), 2391–2402.Google Scholar
  155. 155.
    Zeytin, H. E., Patel, A. C., Rogers, C. J., Canter, D., Hursting, S. D., Schlom, J., et al. (2004). Combination of a poxvirus-based vaccine with a cyclooxygenase-2 inhibitor (celecoxib) elicits antitumor immunity and long-term survival in cea.Tg/min mice. Cancer Research, 64(10), 3668–3678, doi: 10.1158/0008-5472.CAN-03-3878.
  156. 156.
    Csiki, I., Morrow, J. D., Sandler, A., Shyr, Y., Oates, J., Williams, M. K., et al. (2005). Targeting cyclooxygenase-2 in recurrent non-small cell lung cancer: a phase ii trial of celecoxib and docetaxel. Clinical Cancer Research, 11(18), 6634–6640. doi: 10.1158/1078-0432.CCR-05-0436.PubMedGoogle Scholar
  157. 157.
    Ferrari, V., Valcamonico, F., Amoroso, V., Simoncini, E., Vassalli, L., Marpicati, P., et al. (2006). Gemcitabine plus celecoxib (GECO) in advanced pancreatic cancer: a phase ii trial. Cancer Chemotherapy and Pharmacology, 57(2), 185–190. doi: 10.1007/s00280-005-0028-1.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Cancer Immunology Research ProgramPeter MacCallum Cancer CentreEast MelbourneAustralia

Personalised recommendations