Skip to main content
SpringerLink
Log in
Book cover

Immunotherapy of Cancer pp 1–29Cite as

Hypoxic Tumors and Their Effect on Immune Cells and Cancer Therapy

  • Protocol
  • First Online:

Part of the book series: Methods in Molecular Biology ((MIMB,volume 651))

Abstract

The abnormal decrease or the lack of oxygen supply to cells and tissues is called hypoxia. This condition is commonly seen in various diseases such as rheumatoid arthritis and atherosclerosis, also in solid cancers. Pre-clinical and clinical studies have shown that hypoxic cancers are extremely aggressive, resistant to standard therapies (chemotherapy and radiotherapy), and thus very difficult to eradicate. Hypoxia affects both the tumor and the immune cells via various pathways. This review summarizes the most common effects of hypoxia on immune cells that play a key role in the anti-tumor response, the limitation of current therapies, and the potential solutions that were developed for hypoxic malignancies.

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

Protocol
USD   49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Springer Nature is developing a new tool to find and evaluate Protocols. Learn more

References

  1. Crowther, M., Brown, N. J., Bishop, E. T., and Lewis, C. E. (2001) Microenvironmental influence on macrophage regulation of angiogenesis in wounds and malignant tumors. J Leukoc Biol 70, 478–490.

    PubMed  CAS  Google Scholar 

  2. Espey, M. G. (2006) Tumor macrophage redox and effector mechanisms associated with hypoxia. Free Radic Biol Med 41, 1621–1628.

    Article  PubMed  CAS  Google Scholar 

  3. Lukashev, D., Ohta, A., and Sitkovsky, M. (2007) Hypoxia-dependent anti-inflammatory pathways in protection of cancerous tissues. Cancer Metastasis Rev 26, 273–279.

    Article  PubMed  CAS  Google Scholar 

  4. Semenza, G. L. (2001) Hypoxia-inducible factor 1: oxygen homeostasis and disease pathophysiology. Trends Mol Med 7, 345–350.

    Article  PubMed  CAS  Google Scholar 

  5. Zinkernagel, A. S., Johnson, R. S., and Nizet, V. (2007) Hypoxia inducible factor (HIF) function in innate immunity and infection. J Mol Med 85, 1339–1346.

    Article  PubMed  CAS  Google Scholar 

  6. Dayan, F., Mazure, N. M., Brahimi-Horn, M. C., and Pouyssegur, J. (2008) A Dialogue between the Hypoxia-Inducible Factor and the Tumor Microenvironment. Cancer Microenviron 1, 53–68.

    Article  PubMed  CAS  Google Scholar 

  7. Elas, M., Williams, B. B., Parasca, A., Mailer, C., Pelizzari, C. A., Lewis, M. A., River, J. N., Karczmar, G. S., Barth, E. D., and Halpern, H. J. (2003) Quantitative tumor oxymetric images from 4D electron paramagnetic resonance imaging (EPRI): methodology and comparison with blood oxygen level-dependent (BOLD) MRI. Magn Reson Med 49, 682–691.

    Article  PubMed  Google Scholar 

  8. Evans, S. M., Kachur, A. V., Shiue, C. Y., Hustinx, R., Jenkins, W. T., Shive, G. G., Karp, J. S., Alavi, A., Lord, E. M., Dolbier, W. R., Jr., and Koch, C. J. (2000) Noninvasive detection of tumor hypoxia using the 2-nitroimidazole [18F]EF1. J Nucl Med 41, 327–336.

    PubMed  CAS  Google Scholar 

  9. Franco, M., Man, S., Chen, L., Emmenegger, U., Shaked, Y., Cheung, A. M., Brown, A. S., Hicklin, D. J., Foster, F. S., and Kerbel, R. S. (2006) Targeted anti-vascular endothelial growth factor receptor-2 therapy leads to short-term and long-term impairment of vascular function and increase in tumor hypoxia. Cancer Res 66, 3639–3648.

    Article  PubMed  CAS  Google Scholar 

  10. Komar, G., Seppanen, M., Eskola, O., Lindholm, P., Gronroos, T. J., Forsback, S., Sipila, H., Evans, S. M., Solin, O., and Minn, H. (2008) 18F-EF5: a new PET tracer for imaging hypoxia in head and neck cancer. J Nucl Med 49, 1944–1951.

    Article  PubMed  Google Scholar 

  11. Cairns, R. A., Kalliomaki, T., and Hill, R. P. (2001) Acute (cyclic) hypoxia enhances spontaneous metastasis of KHT murine tumors. Cancer Res 61(24), 8903–8908.

    Google Scholar 

  12. Chiche, j., llc, K., Laferriere, j., Trottier, E., Dayan, F., Mazure, N. M., Brahimi-Horn, M. C., and Pouyssegur, j. (2009) Hypoxia-inducible carbonic anhydrase IX and XII promote tumor cell growth by counteracting acidosis through the regulation of the intracellular pH. Cancer Res 69, 358–368.

    Google Scholar 

  13. Wykoff, C. C., Beasley, N. J., Watson, P. H., Turner, K. J., Pastorek, J., Sibtain, A., Wilson, G. D., Turley, H., Talks, K. L., Maxwell, P. H., Pugh, C. W., Ratcliffe, P. J., and Harris, A. L. (2000) Hypoxia-inducible expression of tumor-associated carbonic anhydrases. Cancer Res 60, 7075–7083.

    PubMed  CAS  Google Scholar 

  14. Brahimi-Horn, M. C., Chiche, J., and Pouyssegur, J. (2007) Hypoxia signalling controls metabolic demand. Curr Opin Cell Biol 19, 223–229.

    Article  PubMed  CAS  Google Scholar 

  15. Chiche, J., Ilc, K., Laferriere, J., Trottier, E., Dayan, F., Mazure, N. M., Brahimi-Horn, M. C., and Pouyssegur, J. (2009) Hypoxia-inducible carbonic anhydrase IX and XII promote tumor cell growth by counteracting acidosis through the regulation of the intracellular pH. Cancer Res 69, 358–368.

    Article  PubMed  CAS  Google Scholar 

  16. Martinez-Zaguilan, R., Seftor, E. A., Seftor, R. E., Chu, Y. W., Gillies, R. J., and Hendrix, M. J. (1996) Acidic pH enhances the invasive behavior of human melanoma cells. Clin Exp Metastasis 14, 176–186.

    Article  PubMed  CAS  Google Scholar 

  17. Azad, M. B., Chen, Y., Henson, E. S., Cizeau, J., McMillan-Ward, E., Israels, S. J., and Gibson, S. B. (2008) Hypoxia induces autophagic cell death in apoptosis-competent cells through a mechanism involving BNIP3. Autophagy 4, 195–204.

    PubMed  CAS  Google Scholar 

  18. Zhang, H., Bosch-Marce, M., Shimoda, L. A., Tan, Y. S., Baek, J. H., Wesley, J. B., Gonzalez, F. J., and Semenza, G. L. (2008) Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem 283, 10892–903.

    Article  PubMed  CAS  Google Scholar 

  19. Yen, W. L., and Klionsky, D. J. (2008) How to live long and prosper: autophagy, mitochondria, and aging. Physiology (Bethesda) 23, 248–262.

    Article  CAS  Google Scholar 

  20. Mathew, R., Karantza-Wadsworth, V., and White, E. (2007) Role of autophagy in cancer. Nat Rev Cancer 7, 961–967.

    Article  PubMed  CAS  Google Scholar 

  21. Ceradini, D. J., Kulkarni, A. R., Callaghan, M. J., Tepper, O. M., Bastidas, N., Kleinman, M. E., Capla, J. M., Galiano, R. D., Levine, J. P., and Gurtner, G. C. (2004) Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 10, 858–864.

    Article  PubMed  CAS  Google Scholar 

  22. Du, R., Lu, K. V., Petritsch, C., Liu, P., Ganss, R., Passegue, E., Song, H., Vandenberg, S., Johnson, R. S., Werb, Z., and Bergers, G. (2008) HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 13, 206–220.

    Article  PubMed  CAS  Google Scholar 

  23. Sheng, H., Wang, Y., Jin, Y., Zhang, Q., Zhang, Y., Wang, L., Shen, B., Yin, S., Liu, W., Cui, L., and Li, N. (2008) A critical role of IFNgamma in priming MSC-mediated suppression of T cell proliferation through up-regulation of B7-H1. Cell Res 18, 846–857.

    Article  PubMed  CAS  Google Scholar 

  24. Sevick, E. M., and Jain, R. K. (1989) Viscous resistance to blood flow in solid tumors: effect of hematocrit on intratumor blood viscosity. Cancer Res 49, 3513–3519.

    PubMed  CAS  Google Scholar 

  25. Sitkovsky, M., and Lukashev, D. (2005) Regulation of immune cells by local-tissue oxygen tension: HIF1 alpha and adenosine receptors. Nat Rev Immunol 5, 712–721.

    Article  PubMed  CAS  Google Scholar 

  26. Scortegagna, M., Martin, R. J., Kladney, R. D., Neumann, R. G., and Arbeit, J. M. (2009) Hypoxia-inducible factor-1alpha suppresses squamous carcinogenic progression and epithelial-mesenchymal transition. Cancer Res 69, 2638–2646.

    Article  PubMed  CAS  Google Scholar 

  27. Carmeliet, P. (2000) Mechanisms of angiogenesis and arteriogenesis. Nat Med 6, 389–395.

    Article  PubMed  CAS  Google Scholar 

  28. Helmlinger, G., Endo, M., Ferrara, N., Hlatky, L., and Jain, R. K. (2000) Formation of endothelial cell networks. Nature 405, 139–141.

    Article  PubMed  CAS  Google Scholar 

  29. Pepper, M. S. (1997) Transforming growth factor-beta: vasculogenesis, angiogenesis, and vessel wall integrity. Cytokine Growth Factor Rev 8, 21–43.

    Article  PubMed  CAS  Google Scholar 

  30. Suzuki, A., Kusakai, G., Shimojo, Y., Chen, J., Ogura, T., Kobayashi, M., and Esumi, H. (2005) Involvement of transforming growth factor-beta 1 signaling in hypoxia-induced tolerance to glucose starvation. J Biol Chem 280, 31557–31563.

    Article  PubMed  CAS  Google Scholar 

  31. Sanchez-Elsner, T., Botella, L. M., Velasco, B., Corbi, A., Attisano, L., and Bernabeu, C. (2001) Synergistic cooperation between hypoxia and transforming growth factor-beta pathways on human vascular endothelial growth factor gene expression. J Biol Chem 276, 38527–38535.

    Article  PubMed  CAS  Google Scholar 

  32. Bacac, M., and Stamenkovic, I. (2008) Metastatic cancer cell. Annu Rev Pathol 3, 221–247.

    Google Scholar 

  33. Esteban, M. A., Tran, M. G., Harten, S. K., Hill, P., Castellanos, M. C., Chandra, A., Raval, R., O’Brien T, S., and Maxwell, P. H. (2006) Regulation of E-cadherin expression by VHL and hypoxia-inducible factor. Cancer Res 66, 3567–3575.

    Article  PubMed  CAS  Google Scholar 

  34. Lash, G. E., Fitzpatrick, T. E., and Graham, C. H. (2001) Effect of hypoxia on cellular adhesion to vitronectin and fibronectin. Biochem Biophys Res Commun 287, 622–629.

    Article  PubMed  CAS  Google Scholar 

  35. Ide, T., Kitajima, Y., Miyoshi, A., Ohtsuka, T., Mitsuno, M., Ohtaka, K., and Miyazaki, K. (2007) The hypoxic environment in tumor-stromal cells accelerates pancreatic cancer progression via the activation of paracrine hepatocyte growth factor/c-Met signaling. Ann Surg Oncol 14, 2600–2607.

    Article  PubMed  Google Scholar 

  36. Graeber, T. G., Osmanian, C., Jacks, T., Housman, D. E., Koch, C. J., Lowe, S. W., and Giaccia, A. J. (1996) Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 379, 88–91.

    Article  PubMed  CAS  Google Scholar 

  37. Vaupel, P., Mayer, A., and Hockel, M. (2004) Tumor hypoxia and malignant progression. Methods Enzymol 381, 335–354.

    Article  PubMed  CAS  Google Scholar 

  38. Vaupel, P., and Mayer, A. (2007) Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev 26, 225–239.

    Article  PubMed  CAS  Google Scholar 

  39. Dong, Z., and Wang, J. (2004) Hypoxia selection of death-resistant cells. A role for Bcl-X(L). J Biol Chem 279, 9215–9221.

    Article  PubMed  CAS  Google Scholar 

  40. Bindra, R. S., and Glazer, P. M. (2007) Repression of RAD51 gene expression by E2F4/p130 complexes in hypoxia. Oncogene 26, 2048–2057.

    Article  PubMed  CAS  Google Scholar 

  41. Meng, A. X., Jalali, F., Cuddihy, A., Chan, N., Bindra, R. S., Glazer, P. M., and Bristow, R. G. (2005) Hypoxia down-regulates DNA double strand break repair gene expression in prostate cancer cells. Radiother Oncol 76, 168–176.

    Article  PubMed  CAS  Google Scholar 

  42. Bell, E. L., Klimova, T. A., Eisenbart, J., Schumacker, P. T., and Chandel, N. S. (2007) Mitochondrial reactive oxygen species trigger hypoxia-inducible factor-dependent extension of the replicative life span during hypoxia. Mol Cell Biol 27, 5737–5745.

    Article  PubMed  CAS  Google Scholar 

  43. Siemens, D. R., Hu, N., Sheikhi, A. K., Chung, E., Frederiksen, L. J., Pross, H., and Graham, C. H. (2008) Hypoxia increases tumor cell shedding of MHC class I chain-related molecule: role of nitric oxide. Cancer Res 68, 4746–4753.

    Article  PubMed  CAS  Google Scholar 

  44. Ohnishi, S., Yasuda, T., Kitamura, S., and Nagaya, N. (2007) Effect of hypoxia on gene expression of bone marrow-derived mesenchymal stem cells and mononuclear cells. Stem Cells 25, 1166–1177.

    Article  PubMed  CAS  Google Scholar 

  45. Bingle, L., Brown, N. J., and Lewis, C. E. (2002) The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol 196, 254–265.

    Article  PubMed  CAS  Google Scholar 

  46. Sica, A., Saccani, A., Bottazzi, B., Bernasconi, S., Allavena, P., Gaetano, B., Fei, F., LaRosa, G., Scotton, C., Balkwill, F., and Mantovani, A. (2000) Defective expression of the monocyte chemotactic protein-1 receptor CCR2 in macrophages associated with human ovarian carcinoma. J Immunol 164, 733–738.

    PubMed  CAS  Google Scholar 

  47. Bosco, M. C., Reffo, G., Puppo, M., and Varesio, L. (2004) Hypoxia inhibits the expression of the CCR5 chemokine receptor in macrophages. Cell Immunol 228, 1–7.

    Article  PubMed  CAS  Google Scholar 

  48. Grimshaw, M. J., and Balkwill, F. R. (2001) Inhibition of monocyte and macrophage chemotaxis by hypoxia and inflammation--a potential mechanism. Eur J Immunol 31, 480–489.

    Article  PubMed  CAS  Google Scholar 

  49. Leeper-Woodford, S. K., and Mills, J. W. (1992) Phagocytosis and ATP levels in alveolar macrophages during acute hypoxia. Am J Respir Cell Mol Biol 6, 326–334.

    Article  PubMed  CAS  Google Scholar 

  50. Anand, R. J., Gribar, S. C., Li, J., Kohler, J. W., Branca, M. F., Dubowski, T., Sodhi, C. P., and Hackam, D. J. (2007) Hypoxia causes an increase in phagocytosis by macrophages in a HIF-1alpha-dependent manner. J Leukoc Biol 82, 1257–1265.

    Article  PubMed  CAS  Google Scholar 

  51. Lahat, N., Rahat, M. A., Ballan, M., Weiss-Cerem, L., Engelmayer, M., and Bitterman, H. (2003) Hypoxia reduces CD80 expression on monocytes but enhances their LPS-stimulated TNF-alpha secretion. J Leukoc Biol 74, 197–205.

    Article  PubMed  CAS  Google Scholar 

  52. Murata, Y., Ohteki, T., Koyasu, S., and Hamuro, J. (2002) IFN-gamma and pro-inflammatory cytokine production by antigen-presenting cells is dictated by intracellular thiol redox status regulated by oxygen tension. Eur J Immunol 32, 2866–2873.

    Article  PubMed  CAS  Google Scholar 

  53. Huang, C. J., Haque, I. U., Slovin, P. N., Nielsen, R. B., Fang, X., and Skimming, J. W. (2002) Environmental pH regulates LPS-induced nitric oxide formation in murine macrophages. Nitric Oxide 6, 73–78.

    Article  PubMed  CAS  Google Scholar 

  54. Murata, Y., Shimamura, T., and Hamuro, J. (2002) The polarization of T(h)1/T(h)2 balance is dependent on the intracellular thiol redox status of macrophages due to the distinctive cytokine production. Int Immunol 14, 201–212.

    Article  PubMed  CAS  Google Scholar 

  55. Onita, T., Ji, P. G., Xuan, J. W., Sakai, H., Kanetake, H., Maxwell, P. H., Fong, G. H., Gabril, M. Y., Moussa, M., and Chin, J. L. (2002) Hypoxia-induced, perinecrotic expression of endothelial Per-ARNT-Sim domain protein-1/hypoxia-inducible factor-2alpha correlates with tumor progression, vascularization, and focal macrophage infiltration in bladder cancer. Clin Cancer Res 8, 471–480.

    PubMed  CAS  Google Scholar 

  56. Koga, F., Kageyama, Y., Kawakami, S., Fujii, Y., Hyochi, N., Ando, N., Takizawa, T., Saito, K., Iwai, A., Masuda, H., and Kihara, K. (2004) Prognostic significance of endothelial Per-Arnt-sim domain protein 1/hypoxia-inducible factor-2alpha expression in a subset of tumor associated macrophages in invasive bladder cancer. J Urol 171, 1080–1084.

    Article  PubMed  CAS  Google Scholar 

  57. Burke, B., Giannoudis, A., Corke, K. P., Gill, D., Wells, M., Ziegler-Heitbrock, L., and Lewis, C. E. (2003) Hypoxia-induced gene expression in human macrophages: implications for ischemic tissues and hypoxia-regulated gene therapy. Am J Pathol 163, 1233–1243.

    Article  PubMed  CAS  Google Scholar 

  58. Yun, J. K., McCormick, T. S., Villabona, C., Judware, R. R., Espinosa, M. B., and Lapetina, E. G. (1997) Inflammatory mediators are perpetuated in macrophages resistant to apoptosis induced by hypoxia. Proc Natl Acad Sci U S A 94, 13903–13908.

    Article  PubMed  CAS  Google Scholar 

  59. Kuwabara, K., Ogawa, S., Matsumoto, M., Koga, S., Clauss, M., Pinsky, D. J., Lyn, P., Leavy, J., Witte, L., Joseph-Silverstein, J., and et al. (1995) Hypoxia-mediated induction of acidic/basic fibroblast growth factor and platelet-derived growth factor in mononuclear phagocytes stimulates growth of hypoxic endothelial cells. Proc Natl Acad Sci U S A 92, 4606–4610.

    Article  PubMed  CAS  Google Scholar 

  60. O’Sullivan, C., Lewis, C. E., Harris, A. L., and McGee, J. O. (1993) Secretion of epidermal growth factor by macrophages associated with breast carcinoma. Lancet 342, 148–149.

    Article  PubMed  Google Scholar 

  61. Leek, R. D., Hunt, N. C., Landers, R. J., Lewis, C. E., Royds, J. A., and Harris, A. L. (2000) Macrophage infiltration is associated with VEGF and EGFR expression in breast cancer. J Pathol 190, 430–436.

    Article  PubMed  CAS  Google Scholar 

  62. Sasaki, T., Nakamura, T., Rebhun, R. B., Cheng, H., Hale, K. S., Tsan, R. Z., Fidler, I. J., and Langley, R. R. (2008) Modification of the primary tumor microenvironment by transforming growth factor alpha-epidermal growth factor receptor signaling promotes metastasis in an orthotopic colon cancer model. Am J Pathol 173, 205–216.

    Article  PubMed  CAS  Google Scholar 

  63. Schmeisser, A., Marquetant, R., Illmer, T., Graffy, C., Garlichs, C. D., Bockler, D., Menschikowski, D., Braun–Dullaeus, R., Daniel, W. G., and Strasser, R. H. (2005) The expression of macrophage migration inhibitory factor 1alpha (MIF 1alpha) in human atherosclerotic plaques is induced by different proatherogenic stimuli and associated with plaque instability. Atherosclerosis 178, 83–94.

    Article  PubMed  CAS  Google Scholar 

  64. Compeau, C. G., Ma, J., DeCampos, K. N., Waddell, T. K., Brisseau, G. F., Slutsky, A. S., and Rotstein, O. D. (1994) In situ ischemia and hypoxia enhance alveolar macrophage tissue factor expression. Am J Respir Cell Mol Biol 11, 446–455.

    Article  PubMed  CAS  Google Scholar 

  65. Murdoch, C., Muthana, M., and Lewis, C. E. (2005) Hypoxia regulates macrophage functions in inflammation. J Immunol 175, 6257–6263.

    PubMed  CAS  Google Scholar 

  66. Lewis, J. S., Landers, R. J., Underwood, J. C., Harris, A. L., and Lewis, C. E. (2000) Expression of vascular endothelial growth factor by macrophages is up-regulated in poorly vascularized areas of breast carcinomas. J Pathol 192, 150–158.

    Article  PubMed  CAS  Google Scholar 

  67. Harmey, J. H., Dimitriadis, E., Kay, E., Redmond, H. P., and Bouchier-Hayes, D. (1998) Regulation of macrophage production of vascular endothelial growth factor (VEGF) by hypoxia and transforming growth factor beta-1. Ann Surg Oncol 5, 271–278.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  69. Condeelis, J., and Pollard, J. W. (2006) Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124, 263–266.

    Article  PubMed  CAS  Google Scholar 

  70. Stojadinovic, A., Kiang, J., Smallridge, R., Galloway, R., and Shea-Donohue, T. (1995) Induction of heat-shock protein 72 protects against ischemia/reperfusion in rat small intestine. Gastroenterology 109, 505–515.

    Article  PubMed  CAS  Google Scholar 

  71. Colgan, S. P., Dzus, A. L., and Parkos, C. A. (1996) Epithelial exposure to hypoxia modulates neutrophil transepithelial migration. J Exp Med 184, 1003–1015.

    Article  PubMed  CAS  Google Scholar 

  72. Baggiolini, M. (1998) Chemokines and leukocyte traffic. Nature 392, 565–568.

    Article  PubMed  CAS  Google Scholar 

  73. Bosco, M. C., Puppo, M., Blengio, F., Fraone, T., Cappello, P., Giovarelli, M., and Varesio, L. (2008) Monocytes and dendritic cells in a hypoxic environment: Spotlights on chemotaxis and migration. Immunobiology 213, 733–749.

    Article  PubMed  CAS  Google Scholar 

  74. Mecklenburgh, K. I., Walmsley, S. R., Cowburn, A. S., Wiesener, M., Reed, B. J., Upton, P. D., Deighton, J., Greening, A. P., and Chilvers, E. R. (2002) Involvement of a ferroprotein sensor in hypoxia-mediated inhibition of neutrophil apoptosis. Blood 100, 3008–3016.

    Article  PubMed  CAS  Google Scholar 

  75. Walmsley, S. R., Print, C., Farahi, N., Peyssonnaux, C., Johnson, R. S., Cramer, T., Sobolewski, A., Condliffe, A. M., Cowburn, A. S., Johnson, N., and Chilvers, E. R. (2005) Hypoxia-induced neutrophil survival is mediated by HIF-1alpha-dependent NF-kappaB activity. J Exp Med 201, 105–115.

    Article  PubMed  CAS  Google Scholar 

  76. Wood, J. G., Johnson, J. S., Mattioli, L. F., and Gonzalez, N. C. (1999) Systemic hypoxia promotes leukocyte-endothelial adherence via reactive oxidant generation. J Appl Physiol 87, 1734–1740.

    PubMed  CAS  Google Scholar 

  77. Ginis, I., Mentzer, S. J., and Faller, D. V. (1993) Oxygen tension regulates neutrophil adhesion to human endothelial cells via an LFA-1-dependent mechanism. J Cell Physiol 157, 569–578.

    Article  PubMed  CAS  Google Scholar 

  78. Hannah, S., Mecklenburgh, K., Rahman, I., Bellingan, G. J., Greening, A., Haslett, C., and Chilvers, E. R. (1995) Hypoxia prolongs neutrophil survival in vitro. FEBS Lett 372, 233–237.

    Article  PubMed  CAS  Google Scholar 

  79. Loeffler, D. A., Keng, P. C., Baggs, R. B., and Lord, E. M. (1990) Lymphocytic infiltration and cytotoxicity under hypoxic conditions in the EMT6 mouse mammary tumor. Int J Cancer 45, 462–467.

    Article  PubMed  CAS  Google Scholar 

  80. Allen, D. B., Maguire, J. J., Mahdavian, M., Wicke, C., Marcocci, L., Scheuenstuhl, H., Chang, M., Le, A. X., Hopf, H. W., and Hunt, T. K. (1997) Wound hypoxia and acidosis limit neutrophil bacterial killing mechanisms. Arch Surg 132, 991–996.

    Article  PubMed  CAS  Google Scholar 

  81. Araki, A., Inoue, T., Cragoe, E. J., Jr., and Sendo, F. (1991) Na+/H+ exchange modulates rat neutrophil mediated tumor cytotoxicity. Cancer Res 51, 3212–3216.

    PubMed  CAS  Google Scholar 

  82. Rotstein, O. D., Fiegel, V. D., Simmons, R. L., and Knighton, D. R. (1988) The deleterious effect of reduced pH and hypoxia on neutrophil migration in vitro. J Surg Res 45, 298–303.

    Article  PubMed  CAS  Google Scholar 

  83. Martinez, D., Vermeulen, M., Trevani, A., Ceballos, A., Sabatte, J., Gamberale, R., Alvarez, M. E., Salamone, G., Tanos, T., Coso, O. A., and Geffner, J. (2006) Extracellular acidosis induces neutrophil activation by a mechanism dependent on activation of phosphatidylinositol 3-kinase/Akt and ERK pathways. J Immunol 176, 1163–1171.

    PubMed  CAS  Google Scholar 

  84. Qutub, A. A., and Popel, A. S. (2008) Reactive oxygen species regulate hypoxia-inducible factor 1alpha differentially in cancer and ischemia. Mol Cell Biol 28, 5106–5119.

    Article  PubMed  CAS  Google Scholar 

  85. Gronert, K., Colgan, S. P., and Serhan, C. N. (1998) Characterization of human neutrophil and endothelial cell ligand-operated extracellular acidification rate by microphysiometry: impact of reoxygenation. J Pharmacol Exp Ther 285, 252–261.

    PubMed  CAS  Google Scholar 

  86. Eltzschig, H. K., Thompson, L. F., Karhausen, J., Cotta, R. J., Ibla, J. C., Robson, S. C., and Colgan, S. P. (2004) Endogenous adenosine produced during hypoxia attenuates neutrophil accumulation: coordination by extracellular nucleotide metabolism. Blood 104, 3986–3992.

    Article  PubMed  CAS  Google Scholar 

  87. Eltzschig, H. K., Eckle, T., Mager, A., Kuper, N., Karcher, C., Weissmuller, T., Boengler, K., Schulz, R., Robson, S. C., and Colgan, S. P. (2006) ATP release from activated neutrophils occurs via connexin 43 and modulates adenosine-dependent endothelial cell function. Circ Res 99, 1100–1108.

    Article  PubMed  CAS  Google Scholar 

  88. Rosenberger, P., Schwab, J. M., Mirakaj, V., Masekowsky, E., Mager, A., Morote-Garcia, J. C., Unertl, K., and Eltzschig, H. K. (2009) Hypoxia-inducible factor-dependent induction of netrin-1 dampens inflammation caused by hypoxia. Nat Immunol 10, 195–202.

    Article  PubMed  CAS  Google Scholar 

  89. Ly, N. P., Komatsuzaki, K., Fraser, I. P., Tseng, A. A., Prodhan, P., Moore, K. J., and Kinane, T. B. (2005) Netrin-1 inhibits leukocyte migration in vitro and in vivo. Proc Natl Acad Sci U S A 102, 14729–14734.

    Article  PubMed  CAS  Google Scholar 

  90. Welbourn, C. R., Goldman, G., Paterson, I. S., Valeri, C. R., Shepro, D., and Hechtman, H. B. (1991) Pathophysiology of ischaemia reperfusion injury: central role of the neutrophil. Br J Surg 78, 651–655.

    Article  PubMed  CAS  Google Scholar 

  91. Nagorsen, D., Voigt, S., Berg, E., Stein, H., Thiel, E., and Loddenkemper, C. (2007) Tumor-infiltrating macrophages and dendritic cells in human colorectal cancer: relation to local regulatory T cells, systemic T-cell response against tumor-associated antigens and survival. J Transl Med 5, 62.

    Article  PubMed  CAS  Google Scholar 

  92. Ohm, J. E., Shurin, M. R., Esche, C., Lotze, M. T., Carbone, D. P., and Gabrilovich, D. I. (1999) Effect of vascular endothelial growth factor and FLT3 ligand on dendritic cell generation in vivo. J Immunol 163, 3260–3268.

    PubMed  CAS  Google Scholar 

  93. Oyama, T., Ran, S., Ishida, T., Nadaf, S., Kerr, L., Carbone, D. P., and Gabrilovich, D. I. (1998) Vascular endothelial growth factor affects dendritic cell maturation through the inhibition of nuclear factor-kappa B activation in hemopoietic progenitor cells. J Immunol 160, 1224–1232.

    PubMed  CAS  Google Scholar 

  94. Ohm, J. E., and Carbone, D. P. (2001) VEGF as a mediator of tumor-associated immunodeficiency. Immunol Res 23, 263–272.

    Article  PubMed  CAS  Google Scholar 

  95. Jantsch, J., Chakravortty, D., Turza, N., Prechtel, A. T., Buchholz, B., Gerlach, R. G., Volke, M., Glasner, J., Warnecke, C., Wiesener, M. S., Eckardt, K. U., Steinkasserer, A., Hensel, M., and Willam, C. (2008) Hypoxia and hypoxia-inducible factor-1 alpha modulate lipopolysaccharide-induced dendritic cell activation and function. J Immunol 180, 4697–705.

    PubMed  CAS  Google Scholar 

  96. Elia, A. R., Cappello, P., Puppo, M., Fraone, T., Vanni, C., Eva, A., Musso, T., Novelli, F., Varesio, L., and Giovarelli, M. (2008) Human dendritic cells differentiated in hypoxia down-modulate antigen uptake and change their chemokine expression profile. J Leukoc Biol 84, 1472–1482.

    Article  PubMed  CAS  Google Scholar 

  97. Adema, G. J., Hartgers, F., Verstraten, R., de Vries, E., Marland, G., Menon, S., Foster, J., Xu, Y., Nooyen, P., McClanahan, T., Bacon, K. B., and Figdor, C. G. (1997) A dendritic-cell-derived C-C chemokine that preferentially attracts naive T cells. Nature 387, 713–717.

    Article  PubMed  CAS  Google Scholar 

  98. Vulcano, M., Struyf, S., Scapini, P., Cassatella, M., Bernasconi, S., Bonecchi, R., Calleri, A., Penna, G., Adorini, L., Luini, W., Mantovani, A., Van Damme, J., and Sozzani, S. (2003) Unique regulation of CCL18 production by maturing dendritic cells. J Immunol 170, 3843–3849.

    PubMed  CAS  Google Scholar 

  99. Carr, M. W., Roth, S. J., Luther, E., Rose, S. S., and Springer, T. A. (1994) Monocyte chemoattractant protein 1 acts as a T-lymphocyte chemoattractant. Proc Natl Acad Sci U S A 91, 3652–3656.

    Article  PubMed  CAS  Google Scholar 

  100. Angiolillo, A. L., Sgadari, C., Taub, D. D., Liao, F., Farber, J. M., Maheshwari, S., Kleinman, H. K., Reaman, G. H., and Tosato, G. (1995) Human interferon-inducible protein 10 is a potent inhibitor of angiogenesis in vivo. J Exp Med 182, 155–162.

    Article  PubMed  CAS  Google Scholar 

  101. Zhao, P., Li, X. G., Yang, M., Shao, Q., Wang, D., Liu, S., Song, H., Song, B., Zhang, Y., and Qu, X. (2008) Hypoxia suppresses the production of MMP-9 by human monocyte-derived dendritic cells and requires activation of adenosine receptor A2b via cAMP/PKA signaling pathway. Mol Immunol 45, 2187–2195.

    Article  PubMed  CAS  Google Scholar 

  102. Qu, X., Yang, M. X., Kong, B. H., Qi, L., Lam, Q. L., Yan, S., Li, P., Zhang, M., and Lu, L. (2005) Hypoxia inhibits the migratory capacity of human monocyte-derived dendritic cells. Immunol Cell Biol 83, 668–673.

    Article  PubMed  Google Scholar 

  103. Zhao, W., Darmanin, S., Fu, Q., Chen, J., Cui, H., Wang, J., Okada, F., Hamada, J., Hattori, Y., Kondo, T., Hamuro, J., Asaka, M., and Kobayashi, M. (2005) Hypoxia suppresses the production of matrix metalloproteinases and the migration of human monocyte-derived dendritic cells. Eur J Immunol 35, 3468–3477.

    Article  PubMed  CAS  Google Scholar 

  104. Mancino, A., Schioppa, T., Larghi, P., Pasqualini, F., Nebuloni, M., Chen, I. H., Sozzani, S., Austyn, J. M., Mantovani, A., and Sica, A. (2008) Divergent effects of hypoxia on dendritic cell functions. Blood 112, 3723–3734.

    Article  PubMed  CAS  Google Scholar 

  105. Gottfried, E., Kunz-Schughart, L. A., Ebner, S., Mueller-Klieser, W., Hoves, S., Andreesen, R., Mackensen, A., and Kreutz, M. (2006) Tumor-derived lactic acid modulates dendritic cell activation and antigen expression. Blood 107, 2013–2021.

    Article  PubMed  CAS  Google Scholar 

  106. Panther, E., Corinti, S., Idzko, M., Herouy, Y., Napp, M., la Sala, A., Girolomoni, G., and Norgauer, J. (2003) Adenosine affects expression of membrane molecules, cytokine and chemokine release, and the T-cell stimulatory capacity of human dendritic cells. Blood 101, 3985–3990.

    Article  PubMed  CAS  Google Scholar 

  107. Panther, E., Idzko, M., Herouy, Y., Rheinen, H., Gebicke-Haerter, P. J., Mrowietz, U., Dichmann, S., and Norgauer, J. (2001) Expression and function of adenosine receptors in human dendritic cells. Faseb J 15, 1963–1970.

    Article  PubMed  CAS  Google Scholar 

  108. Chen, L., Fredholm, B. B., and Jondal, M. (2008) Adenosine, through the A1 receptor, inhibits vesicular MHC class I cross-presentation by resting DC. Mol Immunol 45, 2247–2254.

    Article  PubMed  CAS  Google Scholar 

  109. Ricciardi, A., Elia, A. R., Cappello, P., Puppo, M., Vanni, C., Fardin, P., Eva, A., Munroe, D., Wu, X., Giovarelli, M., and Varesio, L. (2008) Transcriptome of hypoxic immature dendritic cells: modulation of chemokine/receptor expression. Mol Cancer Res 6, 175–185.

    Article  PubMed  CAS  Google Scholar 

  110. Vermeulen, M., Giordano, M., Trevani, A. S., Sedlik, C., Gamberale, R., Fernandez-Calotti, P., Salamone, G., Raiden, S., Sanjurjo, J., and Geffner, J. R. (2004) Acidosis improves uptake of antigens and MHC class I-restricted presentation by dendritic cells. J Immunol 172, 3196–3204.

    PubMed  CAS  Google Scholar 

  111. Makino, Y., Nakamura, H., Ikeda, E., Ohnuma, K., Yamauchi, K., Yabe, Y., Poellinger, L., Okada, Y., Morimoto, C., and Tanaka, H. (2003) Hypoxia–inducible factor regulates survival of antigen receptor-driven T cells. J Immunol 171, 6534–6540.

    PubMed  CAS  Google Scholar 

  112. Biju, M. P., Neumann, A. K., Bensinger, S. J., Johnson, R. S., Turka, L. A., and Haase, V. H. (2004) Vhlh gene deletion induces Hif-1-mediated cell death in thymocytes. Mol Cell Biol 24, 9038–9047.

    Article  PubMed  CAS  Google Scholar 

  113. Sitkovsky, M. V., Kjaergaard, J., Lukashev, D., and Ohta, A. (2008) Hypoxia-adenosinergic immunosuppression: tumor protection by T regulatory cells and cancerous tissue hypoxia. Clin Cancer Res 14, 5947–5952.

    Article  PubMed  CAS  Google Scholar 

  114. Atkuri, K. R., Herzenberg, L. A., and Herzenberg, L. A. (2005) Culturing at atmospheric oxygen levels impacts lymphocyte function. Proc Natl Acad Sci U S A 102, 3756–3759.

    Article  PubMed  CAS  Google Scholar 

  115. Conforti, L., Petrovic, M., Mohammad, D., Lee, S., Ma, Q., Barone, S., and Filipovich, A. H. (2003) Hypoxia regulates expression and activity of Kv1.3 channels in T lymphocytes: a possible role in T cell proliferation. J Immunol 170, 695–702.

    PubMed  CAS  Google Scholar 

  116. Caldwell, C. C., Kojima, H., Lukashev, D., Armstrong, J., Farber, M., Apasov, S. G., and Sitkovsky, M. V. (2001) Differential effects of physiologically relevant hypoxic conditions on T lymphocyte development and effector functions. J Immunol 167, 6140–6149.

    PubMed  CAS  Google Scholar 

  117. Neumann, A. K., Yang, J., Biju, M. P., Joseph, S. K., Johnson, R. S., Haase, V. H., Freedman, B. D., and Turka, L. A. (2005) Hypoxia inducible factor 1 alpha regulates T cell receptor signal transduction. Proc Natl Acad Sci U S A 102, 17071–17076.

    Article  PubMed  CAS  Google Scholar 

  118. Chandy, K. G., DeCoursey, T. E., Cahalan, M. D., McLaughlin, C., and Gupta, S. (1984) Voltage-gated potassium channels are required for human T lymphocyte activation. J Exp Med 160, 369–385.

    Article  PubMed  CAS  Google Scholar 

  119. Zuckerberg, A. L., Goldberg, L. I., and Lederman, H. M. (1994) Effects of hypoxia on interleukin-2 mRNA expression by T lymphocytes. Crit Care Med 22, 197–203.

    Article  PubMed  CAS  Google Scholar 

  120. Naldini, A., Carraro, F., Silvestri, S., and Bocci, V. (1997) Hypoxia affects cytokine production and proliferative responses by human peripheral mononuclear cells. J Cell Physiol 173, 335–342.

    Article  PubMed  CAS  Google Scholar 

  121. Kim, H., Peng, G., Hicks, J. M., Weiss, H. L., Van Meir, E. G., Brenner, M. K., and Yotnda, P. (2008) Engineering human tumor-specific cytotoxic T cells to function in a hypoxic environment. Mol Ther 16, 599–606.

    Article  PubMed  CAS  Google Scholar 

  122. Carraro, F., Pucci, A., Pellegrini, M., Pelicci, P. G., Baldari, C. T., and Naldini, A. (2007) p66Shc is involved in promoting HIF-1alpha accumulation and cell death in hypoxic T cells. J Cell Physiol 211, 439–447.

    Article  PubMed  CAS  Google Scholar 

  123. Kiang, J. G., Krishnan, S., Lu, X., and Li, Y. (2008) Inhibition of inducible nitric-oxide synthase protects human T cells from hypoxia-induced apoptosis. Mol Pharmacol 73, 738–747.

    Article  PubMed  CAS  Google Scholar 

  124. Heinzman, J. M., Brower, S. L., and Bush, J. E. (2008) Comparison of angiogenesis-related factor expression in primary tumor cultures under normal and hypoxic growth conditions. Cancer Cell Int 8, 11.

    Article  PubMed  CAS  Google Scholar 

  125. Lukashev, D., Klebanov, B., Kojima, H., Grinberg, A., Ohta, A., Berenfeld, L., Wenger, R. H., Ohta, A., and Sitkovsky, M. (2006) Cutting edge: hypoxia-inducible factor 1alpha and its activation-inducible short isoform I.1 negatively regulate functions of CD4+ and CD8+ T lymphocytes. J Immunol 177, 4962–4965.

    PubMed  CAS  Google Scholar 

  126. Fischer, K., Hoffmann, P., Voelkl, S., Meidenbauer, N., Ammer, J., Edinger, M., Gottfried, E., Schwarz, S., Rothe, G., Hoves, S., Renner, K., Timischl, B., Mackensen, A., Kunz-Schughart, L., Andreesen, R., Krause, S. W., and Kreutz, M. (2007) Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 109, 3812–3819.

    Article  PubMed  CAS  Google Scholar 

  127. Loeffler, D. A., Juneau, P. L., and Masserant, S. (1992) Influence of tumour physico-chemical conditions on interleukin-2-stimulated lymphocyte proliferation. Br J Cancer 66, 619–622.

    Article  PubMed  CAS  Google Scholar 

  128. Loeffler, D. A., Juneau, P. L., and Heppner, G. H. (1991) Natural killer-cell activity under conditions reflective of tumor micro-environment. Int J Cancer 48, 895–899.

    Article  PubMed  CAS  Google Scholar 

  129. Severin, T., Muller, B., Giese, G., Uhl, B., Wolf, B., Hauschildt, S., and Kreutz, W. (1994) pH-dependent LAK cell cytotoxicity. Tumour Biol 15, 304–310.

    Article  PubMed  CAS  Google Scholar 

  130. Muller, B., Fischer, B., and Kreutz, W. (2000) An acidic microenvironment impairs the generation of non-major histocompatibility complex-restricted killer cells. Immunology 99, 375–384.

    Article  PubMed  CAS  Google Scholar 

  131. Fischer, B., Muller, B., Fisch, P., and Kreutz, W. (2000) An acidic microenvironment inhibits antitumoral non-major histocompatibility complex-restricted cytotoxicity: implications for cancer immunotherapy. J Immunother 23, 196–207.

    Article  PubMed  CAS  Google Scholar 

  132. Valko, M., Izakovic, M., Mazur, M., Rhodes, C. J., and Telser, J. (2004) Role of oxygen radicals in DNA damage and cancer incidence. Mol Cell Biochem 266, 37–56.

    Article  PubMed  CAS  Google Scholar 

  133. Allan, I. M., Lunec, J., Salmon, M., and Bacon, P. A. (1987) Reactive oxygen species selectively deplete normal T lymphocytes via a hydroxyl radical dependent mechanism. Scand J Immunol 26, 47–53.

    Article  PubMed  CAS  Google Scholar 

  134. Hildeman, D. A. (2004) Regulation of T-cell apoptosis by reactive oxygen species. Free Radic Biol Med 36, 1496–1504.

    Article  PubMed  CAS  Google Scholar 

  135. Kwon, J., Devadas, S., and Williams, M. S. (2003) T cell receptor-stimulated generation of hydrogen peroxide inhibits MEK-ERK activation and lck serine phosphorylation. Free Radic Biol Med 35, 406–417.

    Article  PubMed  CAS  Google Scholar 

  136. Jackson, S. H., Devadas, S., Kwon, J., Pinto, L. A., and Williams, M. S. (2004) T cells express a phagocyte-type NADPH oxidase that is activated after T cell receptor stimulation. Nat Immunol 5, 818–827.

    Article  PubMed  CAS  Google Scholar 

  137. Cauley, L. S., Miller, E. E., Yen, M., and Swain, S. L. (2000) Superantigen-induced CD4 T cell tolerance mediated by myeloid cells and IFN-gamma. J Immunol 165, 6056–6066.

    PubMed  CAS  Google Scholar 

  138. Hansson, M., Romero, A., Thoren, F., Hermodsson, S., and Hellstrand, K. (2004) Activation of cytotoxic lymphocytes by interferon-alpha: role of oxygen radical-producing mononuclear phagocytes. J Leukoc Biol 76, 1207–1213.

    Article  PubMed  CAS  Google Scholar 

  139. Schmielau, J., and 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 Res 61, 4756–4760.

    PubMed  CAS  Google Scholar 

  140. Fulton, A. M., and Chong, Y. C. (1992) The role of macrophage-derived TNFa in the induction of sublethal tumor cell DNA damage. Carcinogenesis 13, 77–81.

    Article  PubMed  CAS  Google Scholar 

  141. Nambiar, M. P., Fisher, C. U., Enyedy, E. J., Warke, V. G., Kumar, A., and Tsokos, G. C. (2002) Oxidative stress is involved in the heat stress-induced downregulation of TCR zeta chain expression and TCR/CD3-mediated [Ca(2+)](i) response in human T-lymphocytes. Cell Immunol 215, 151–161.

    Article  PubMed  CAS  Google Scholar 

  142. Nindl, G., Peterson, N. R., Hughes, E. F., Waite, L. R., and Johnson, M. T. (2004) Effect of hydrogen peroxide on proliferation, apoptosis and interleukin-2 production of Jurkat T cells. Biomed Sci Instrum 40, 123–128.

    PubMed  CAS  Google Scholar 

  143. Gringhuis, S. I., Papendrecht-van der Voort, E. A., Leow, A., Nivine Levarht, E. W., Breedveld, F. C., and Verweij, C. L. (2002) Effect of redox balance alterations on cellular localization of LAT and downstream T-cell receptor signaling pathways. Mol Cell Biol 22, 400–411.

    Article  PubMed  CAS  Google Scholar 

  144. Takahashi, A., Hanson, M. G., Norell, H. R., Havelka, A. M., Kono, K., Malmberg, K. J., and Kiessling, R. V. (2005) Preferential cell death of CD8+ effector memory (CCR7-CD45RA-) T cells by hydrogen peroxide-induced oxidative stress. J Immunol 174, 6080–6087.

    PubMed  CAS  Google Scholar 

  145. Huang, S., Apasov, S., Koshiba, M., and Sitkovsky, M. (1997) Role of A2a extracellular adenosine receptor-mediated signaling in adenosine-mediated inhibition of T-cell activation and expansion. Blood 90, 1600–1610.

    PubMed  CAS  Google Scholar 

  146. Hoskin, D. W., Mader, J. S., Furlong, S. J., Conrad, D. M., and Blay, J. (2008) Inhibition of T cell and natural killer cell function by adenosine and its contribution to immune evasion by tumor cells (Review). Int J Oncol 32, 527–535.

    PubMed  CAS  Google Scholar 

  147. Ohta, A., Gorelik, E., Prasad, S. J., Ronchese, F., Lukashev, D., Wong, M. K., Huang, X., Caldwell, S., Liu, K., Smith, P., Chen, J. F., Jackson, E. K., Apasov, S., Abrams, S., and Sitkovsky, M. (2006) A2A adenosine receptor protects tumors from antitumor T cells. Proc Natl Acad Sci U S A 103, 13132–13137.

    Article  PubMed  CAS  Google Scholar 

  148. Sitkovsky, M. V., and Ohta, A. (2005) The ‘danger’ sensors that STOP the immune response: the A2 adenosine receptors? Trends Immunol 26, 299–304.

    Article  PubMed  CAS  Google Scholar 

  149. Ohta, A., Kjaergaard, J., Sharma, S., Mohsin, M., Goel, N., Madasu, M., Fradkov, E., Ohta, A., and Sitkovsky, M. (2009) In vitro induction of T cells that are resistant to A2 adenosine receptor-mediated immunosuppression. Br J Pharmacol 156, 297–306.

    Article  PubMed  CAS  Google Scholar 

  150. Raskovalova, T., Huang, X., Sitkovsky, M., Zacharia, L. C., Jackson, E. K., and Gorelik, E. (2005) Gs protein-coupled adenosine receptor signaling and lytic function of activated NK cells. J Immunol 175, 4383–4391.

    PubMed  CAS  Google Scholar 

  151. Lokshin, A., Raskovalova, T., Huang, X., Zacharia, L. C., Jackson, E. K., and Gorelik, E. (2006) Adenosine-mediated inhibition of the cytotoxic activity and cytokine production by activated natural killer cells. Cancer Res 66, 7758–7765.

    Article  PubMed  CAS  Google Scholar 

  152. Raskovalova, T., Lokshin, A., Huang, X., Jackson, E. K., and Gorelik, E. (2006) Adenosine-mediated inhibition of cytotoxic activity and cytokine production by IL-2/NKp46-activated NK cells: involvement of protein kinase A isozyme I (PKA I). Immunol Res 36, 91–99.

    Article  PubMed  CAS  Google Scholar 

  153. Sitkovsky, M. V. (2009) T regulatory cells: hypoxia-adenosinergic suppression and re-direction of the immune response. Trends Immunol 30, 102–108.

    Article  PubMed  CAS  Google Scholar 

  154. Ben-Shoshan, J., Maysel-Auslender, S., Mor, A., Keren, G., and George, J. (2008) Hypoxia controls CD4+CD25+ regulatory T-cell homeostasis via hypoxia-inducible factor-1alpha. Eur J Immunol 38, 2412–2418.

    Article  PubMed  CAS  Google Scholar 

  155. Eltzschig, H. K., Ibla, J. C., Furuta, G. T., Leonard, M. O., Jacobson, K. A., Enjyoji, K., Robson, S. C., and Colgan, S. P. (2003) Coordinated adenine nucleotide phosphohydrolysis and nucleoside signaling in posthypoxic endothelium: role of ectonucleotidases and adenosine A2B receptors. J Exp Med 198, 783–796.

    Article  PubMed  CAS  Google Scholar 

  156. Mrena, J., Wiksten, J. P., Thiel, A., Kokkola, A., Pohjola, L., Lundin, J., Nordling, S., Ristimaki, A., and Haglund, C. (2005) Cyclooxygenase-2 is an independent prognostic factor in gastric cancer and its expression is regulated by the messenger RNA stability factor HuR. Clin Cancer Res 11, 7362–7368.

    Article  PubMed  CAS  Google Scholar 

  157. Su, Y., Huang, X., Raskovalova, T., Zacharia, L., Lokshin, A., Jackson, E., and Gorelik, E. (2008) Cooperation of adenosine and prostaglandin E2 (PGE2) in amplification of cAMP-PKA signaling and immunosuppression. Cancer Immunol Immunother 57, 1611–1623.

    Article  PubMed  CAS  Google Scholar 

  158. Kundu, N., Walser, T. C., Ma, X., and Fulton, A. M. (2005) Cyclooxygenase inhibitors modulate NK activities that control metastatic disease. Cancer Immunol Immunother 54, 981–987.

    Article  PubMed  CAS  Google Scholar 

  159. Kojima, H., Gu, H., Nomura, S., Caldwell, C. C., Kobata, T., Carmeliet, P., Semenza, G. L., and Sitkovsky, M. V. (2002) Abnormal B lymphocyte development and autoimmunity in hypoxia-inducible factor 1alpha -deficient chimeric mice. Proc Natl Acad Sci U S A 99, 2170–2174.

    Article  PubMed  CAS  Google Scholar 

  160. Kojima, H., Jones, B. T., Chen, J., Cascalho, M., and Sitkovsky, M. V. (2004) Hypoxia-inducible factor 1alpha-deficient chimeric mice as a model to study abnormal B lymphocyte development and autoimmunity. Methods Enzymol 381, 218–229.

    Article  PubMed  CAS  Google Scholar 

  161. Piovan, E., Tosello, V., Indraccolo, S., Masiero, M., Persano, L., Esposito, G., Zamarchi, R., Ponzoni, M., Chieco-Bianchi, L., Dalla-Favera, R., and Amadori, A. (2007) Differential regulation of hypoxia-induced CXCR4 triggering during B-cell development and lymphomagenesis. Cancer Res 67, 8605–8614.

    Article  PubMed  CAS  Google Scholar 

  162. Goda, N., Ryan, H. E., Khadivi, B., McNulty, W., Rickert, R. C., and Johnson, R. S. (2003) Hypoxia-inducible factor 1alpha is essential for cell cycle arrest during hypoxia. Mol Cell Biol 23, 359–369.

    Article  PubMed  CAS  Google Scholar 

  163. Hockel, M., and Vaupel, P. (2001) Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst 93, 266–276.

    Article  PubMed  CAS  Google Scholar 

  164. Isa, A. Y., Ward, T. H., West, C. M., Slevin, N. J., and Homer, J. J. (2006) Hypoxia in head and neck cancer. Br J Radiol 79, 791–798.

    Article  PubMed  CAS  Google Scholar 

  165. Albertoni, M., Shaw, P. H., Nozaki, M., Godard, S., Tenan, M., Hamou, M. F., Fairlie, D. W., Breit, S. N., Paralkar, V. M., de Tribolet, N., Van Meir, E. G., and Hegi, M. E. (2002) Anoxia induces macrophage inhibitory cytokine-1 (MIC-1) in glioblastoma cells independently of p53 and HIF-1. Oncogene 21, 4212–4219.

    Article  PubMed  CAS  Google Scholar 

  166. Erler, J. T., Cawthorne, C. J., Williams, K. J., Koritzinsky, M., Wouters, B. G., Wilson, C., Miller, C., Demonacos, C., Stratford, I. J., and Dive, C. (2004) Hypoxia-mediated down-regulation of Bid and Bax in tumors occurs via hypoxia-inducible factor 1-dependent and -independent mechanisms and contributes to drug resistance. Mol Cell Biol 24, 2875–2889.

    Article  PubMed  CAS  Google Scholar 

  167. Comerford, K. M., Wallace, T. J., Karhausen, J., Louis, N. A., Montalto, M. C., and Colgan, S. P. (2002) Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene. Cancer Res 62, 3387–3394.

    PubMed  CAS  Google Scholar 

  168. Reichert, M., Steinbach, J. P., Supra, P., and Weller, M. (2002) Modulation of growth and radiochemosensitivity of human malignant glioma cells by acidosis. Cancer 95, 1113–1119.

    Article  PubMed  CAS  Google Scholar 

  169. Le, Q. T., Taira, A., Budenz, S., Jo Dorie, M., Goffinet, D. R., Fee, W. E., Goode, R., Bloch, D., Koong, A., Martin Brown, J., and Pinto, H. A. (2006) Mature results from a randomized Phase II trial of cisplatin plus 5-fluorouracil and radiotherapy with or without tirapazamine in patients with resectable Stage IV head and neck squamous cell carcinomas. Cancer 106, 1940–1949.

    Article  PubMed  CAS  Google Scholar 

  170. Steward, W. P., Middleton, M., Benghiat, A., Loadman, P. M., Hayward, C., Waller, S., Ford, S., Halbert, G., Patterson, L. H., and Talbot, D. (2007) The use of pharmacokinetic and pharmacodynamic end points to determine the dose of AQ4N, a novel hypoxic cell cytotoxin, given with fractionated radiotherapy in a phase I study. Ann Oncol 18, 1098–1103.

    Article  PubMed  CAS  Google Scholar 

  171. Albertella, M. R., Loadman, P. M., Jones, P. H., Phillips, R. M., Rampling, R., Burnet, N., Alcock, C., Anthoney, A., Vjaters, E., Dunk, C. R., Harris, P. A., Wong, A., Lalani, A. S., and Twelves, C. J. (2008) Hypoxia-selective targeting by the bioreductive prodrug AQ4N in patients with solid tumors: results of a phase I study. Clin Cancer Res 14, 1096–1104.

    Article  PubMed  CAS  Google Scholar 

  172. Puppo, M., Battaglia, F., Ottaviano, C., Delfino, S., Ribatti, D., Varesio, L., and Bosco, M. C. (2008) Topotecan inhibits vascular endothelial growth factor production and angiogenic activity induced by hypoxia in human neuroblastoma by targeting hypoxia-inducible factor-1alpha and -2alpha. Mol Cancer Ther 7, 1974–1984.

    Article  PubMed  CAS  Google Scholar 

  173. Shin, D. H., Chun, Y. S., Lee, D. S., Huang, L. E., and Park, J. W. (2008) Bortezomib inhibits tumor adaptation to hypoxia by stimulating the FIH-mediated repression of hypoxia-inducible factor-1. Blood 111, 3131–3136.

    Article  PubMed  CAS  Google Scholar 

  174. Hirst, D. G. (1986) Anemia: a problem or an opportunity in radiotherapy? Int J Radiat Oncol Biol Phys 12, 2009–2017.

    Article  PubMed  CAS  Google Scholar 

  175. Bokemeyer, C., Aapro, M. S., Courdi, A., Foubert, J., Link, H., Osterborg, A., Repetto, L., and Soubeyran, P. (2007) EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer: 2006 update. Eur J Cancer 43, 258–270.

    Article  PubMed  CAS  Google Scholar 

  176. Frederiksen, L. J., Sullivan, R., Maxwell, L. R., Macdonald-Goodfellow, S. K., Adams, M. A., Bennett, B. M., Siemens, D. R., and Graham, C. H. (2007) Chemosensitization of cancer in vitro and in vivo by nitric oxide signaling. Clin Cancer Res 13, 2199–2206.

    Article  PubMed  CAS  Google Scholar 

  177. Thomas, G. V., Tran, C., Mellinghoff, I. K., Welsbie, D. S., Chan, E., Fueger, B., Czernin, J., and Sawyers, C. L. (2006) Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. Nat Med 12, 122–127.

    Article  PubMed  CAS  Google Scholar 

  178. Taghian, A. G., Abi-Raad, R., Assaad, S. I., Casty, A., Ancukiewicz, M., Yeh, E., Molokhia, P., Attia, K., Sullivan, T., Kuter, I., Boucher, Y., and Powell, S. N. (2005) Paclitaxel decreases the interstitial fluid pressure and improves oxygenation in breast cancers in patients treated with neoadjuvant chemotherapy: clinical implications. J Clin Oncol 23, 1951–1961.

    Article  PubMed  CAS  Google Scholar 

  179. Overgaard, J., Hansen, H. S., Overgaard, M., Bastholt, L., Berthelsen, A., Specht, L., Lindelov, B., and Jorgensen, K. (1998) A randomized double-blind phase III study of nimorazole as a hypoxic radiosensitizer of primary radiotherapy in supraglottic larynx and pharynx carcinoma. Results of the Danish Head and Neck Cancer Study (DAHANCA) Protocol 5-85. Radiother Oncol 46, 135–146.

    Article  PubMed  CAS  Google Scholar 

  180. Overgaard, J., Eriksen, J. G., Nordsmark, M., Alsner, J., and Horsman, M. R. (2005) Plasma osteopontin, hypoxia, and response to the hypoxia sensitiser nimorazole in radiotherapy of head and neck cancer: results from the DAHANCA 5 randomised double-blind placebo-controlled trial. Lancet Oncol 6, 757–764.

    Article  PubMed  CAS  Google Scholar 

  181. Overgaard, J. (1994) Clinical evaluation of nitroimidazoles as modifiers of hypoxia in solid tumors. Oncol Res 6, 509–518.

    PubMed  CAS  Google Scholar 

  182. van Laarhoven, H. W., Kaanders, J. H., Lok, J., Peeters, W. J., Rijken, P. F., Wiering, B., Ruers, T. J., Punt, C. J., Heerschap, A., and van der Kogel, A. J. (2006) Hypoxia in relation to vasculature and proliferation in liver metastases in patients with colorectal cancer. Int J Radiat Oncol Biol Phys 64, 473–482.

    Article  PubMed  Google Scholar 

  183. Hoogsteen, I. J., Pop, L. A., Marres, H. A., Merkx, M. A., van den Hoogen, F. J., van der Kogel, A. J., and Kaanders, J. H. (2006) Oxygen-modifying treatment with ARCON reduces the prognostic significance of hemoglobin in squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 64, 83–89.

    Article  PubMed  CAS  Google Scholar 

  184. Bernier, J., Denekamp, J., Rojas, A., Minatel, E., Horiot, J., Hamers, H., Antognoni, P., Dahl, O., Richaud, P., van Glabbeke, M., and Pierart, M. (2000) ARCON: accelerated radiotherapy with carbogen and nicotinamide in head and neck squamous cell carcinomas. The experience of the Co-operative group of radiotherapy of the european organization for research and treatment of cancer (EORTC). Radiother Oncol 55, 111–119.

    Article  PubMed  CAS  Google Scholar 

  185. Miyake, K., Shimada, M., Nishioka, M., Sugimoto, K., Batmunkh, E., Uto, Y., Nagasawa, H., and Hori, H. (2008) The novel hypoxic cell radiosensitizer, TX-1877 has antitumor activity through suppression of angiogenesis and inhibits liver metastasis on xenograft model of pancreatic cancer. Cancer Lett 272, 325–335.

    Article  PubMed  CAS  Google Scholar 

  186. Oshikawa, T., Okamoto, M., Ahmed, S. U., Furuichi, S., Tano, T., Sasai, A., Kan, S., Kasai, S., Uto, Y., Nagasawa, H., Hori, H., and Sato, M. (2005) TX-1877, a bifunctional hypoxic cell radiosensitizer, enhances anticancer host response: immune cell migration and nitric oxide production. Int J Cancer 116, 571–578.

    Article  PubMed  CAS  Google Scholar 

  187. De Ridder, M., Jiang, H., Van Esch, G., Law, K., Monsaert, C., Van den Berge, D. L., Verellen, D., Verovski, V. N., and Storme, G. A. (2008) IFN-gamma+ CD8+ T lymphocytes: possible link between immune and radiation responses in tumor-relevant hypoxia. Int J Radiat Oncol Biol Phys 71, 647–651.

    Article  PubMed  CAS  Google Scholar 

  188. Janssens, M. Y., Van den Berge, D. L., Verovski, V. N., Monsaert, C., and Storme, G. A. (1998) Activation of inducible nitric oxide synthase results in nitric oxide-mediated radiosensitization of hypoxic EMT-6 tumor cells. Cancer Res 58, 5646–5648.

    PubMed  CAS  Google Scholar 

  189. Wilson, W. R., Tercel, M., Anderson, R. F., and Denny, W. A. (1998) Radiation-activated prodrugs as hypoxia-selective cytotoxins: model studies with nitroarylmethyl quaternary salts. Anticancer Drug Des 13, 663–685.

    PubMed  CAS  Google Scholar 

  190. Kriste, A. G., Tercel, M., Anderson, R. F., Ferry, D. M., and Wilson, W. R. (2002) Pathways of reductive fragmentation of heterocyclic nitroarylmethyl quaternary ammonium prodrugs of mechlorethamine. Radiat Res 158, 753–762.

    Article  PubMed  CAS  Google Scholar 

  191. Suh, J. H., Stea, B., Nabid, A., Kresl, J. J., Fortin, A., Mercier, J. P., Senzer, N., Chang, E. L., Boyd, A. P., Cagnoni, P. J., and Shaw, E. (2006) Phase III study of efaproxiral as an adjunct to whole-brain radiation therapy for brain metastases. J Clin Oncol 24, 106–114.

    Article  PubMed  CAS  Google Scholar 

  192. Mayer, R., Hamilton-Farrell, M. R., van der Kleij, A. J., Schmutz, J., Granstrom, G., Sicko, Z., Melamed, Y., Carl, U. M., Hartmann, K. A., Jansen, E. C., Ditri, L., and Sminia, P. (2005) Hyperbaric oxygen and radiotherapy. Strahlenther Onkol 181, 113–123.

    Article  PubMed  Google Scholar 

  193. Bennett, M., Feldmeier, J., Smee, R., and Milross, C. (2008) Hyperbaric oxygenation for tumour sensitisation to radiotherapy: a systematic review of randomised controlled trials. Cancer Treat Rev 34, 577–591.

    Article  PubMed  CAS  Google Scholar 

  194. Zaffaroni, N., Fiorentini, G., and De Giorgi, U. (2001) Hyperthermia and hypoxia: new developments in anticancer chemotherapy. Eur J Surg Oncol 27, 340–342.

    Article  PubMed  CAS  Google Scholar 

  195. Kuemmerle, A., Decosterd, L. A., Buclin, T., Lienard, D., Stupp, R., Chassot, P. G., Mosimann, F., and Lejeune, F. (2009) A phase I pharmacokinetic study of hypoxic abdominal stop-flow perfusion with gemcitabine in patients with advanced pancreatic cancer and refractory malignant ascites. Cancer Chemother Pharmacol 63, 331–341.

    Article  PubMed  CAS  Google Scholar 

  196. Trinh, Q. T., Austin, E. A., Murray, D. M., Knick, V. C., and Huber, B. E. (1995) Enzyme/prodrug gene therapy: comparison of cytosine deaminase/5-fluorocytosine versus thymidine kinase/ganciclovir enzyme/prodrug systems in a human colorectal carcinoma cell line. Cancer Res 55, 4808–4812.

    PubMed  CAS  Google Scholar 

  197. Dachs, G. U., Patterson, A. V., Firth, J. D., Ratcliffe, P. J., Townsend, K. M., Stratford, I. J., and Harris, A. L. (1997) Targeting gene expression to hypoxic tumor cells. Nat Med 3, 515–520.

    Article  PubMed  CAS  Google Scholar 

  198. Shibata, T., Giaccia, A. J., and Brown, J. M. (2002) Hypoxia-inducible regulation of a prodrug-activating enzyme for tumor-specific gene therapy. Neoplasia 4, 40–48.

    Article  PubMed  CAS  Google Scholar 

  199. Post, D. E., Devi, N. S., Li, Z., Brat, D. J., Kaur, B., Nicholson, A., Olson, J. J., Zhang, Z., and Van Meir, E. G. (2004) Cancer therapy with a replicating oncolytic adenovirus targeting the hypoxic microenvironment of tumors. Clin Cancer Res 10, 8603–8612.

    Article  PubMed  CAS  Google Scholar 

  200. Hernandez-Alcoceba, R., Pihalja, M., Qian, D., and Clarke, M. F. (2002) New oncolytic adenoviruses with hypoxia- and estrogen receptor-regulated replication. Hum Gene Ther 13, 1737–1750.

    Article  PubMed  CAS  Google Scholar 

  201. Binley, K., Askham, Z., Martin, L., Spearman, H., Day, D., Kingsman, S., and Naylor, S. (2003) Hypoxia-mediated tumour targeting. Gene Ther 10, 540–549.

    Article  PubMed  CAS  Google Scholar 

  202. Koshikawa, N., Takenaga, K., Tagawa, M., and Sakiyama, S. (2000) Therapeutic efficacy of the suicide gene driven by the promoter of vascular endothelial growth factor gene against hypoxic tumor cells. Cancer Res 60, 2936–2941.

    PubMed  CAS  Google Scholar 

  203. Liu, S. C., Minton, N. P., Giaccia, A. J., and Brown, J. M. (2002) Anticancer efficacy of systemically delivered anaerobic bacteria as gene therapy vectors targeting tumor hypoxia/necrosis. Gene Ther 9, 291–296.

    Article  PubMed  CAS  Google Scholar 

  204. Li, Z., Fallon, J., Mandeli, J., Wetmur, J., and Woo, S. L. (2008) A genetically enhanced anaerobic bacterium for oncopathic therapy of pancreatic cancer. J Natl Cancer Inst 100, 1389–400.

    Article  PubMed  CAS  Google Scholar 

  205. Brouwers, A. H., van Eerd, J. E., Frielink, C., Oosterwijk, E., Oyen, W. J., Corstens, F. H., and Boerman, O. C. (2004) Optimization of radioimmunotherapy of renal cell carcinoma: labeling of monoclonal antibody cG250 with 131I, 90Y, 177Lu, or 186Re. J Nucl Med 45, 327–337.

    PubMed  CAS  Google Scholar 

  206. Bleumer, I., Oosterwijk, E., Oosterwijk-Wakka, J. C., Voller, M. C., Melchior, S., Warnaar, S. O., Mala, C., Beck, J., and Mulders, P. F. (2006) A clinical trial with chimeric monoclonal antibody WX-G250 and low dose interleukin-2 pulsing scheme for advanced renal cell carcinoma. J Urol 175, 57–62.

    Article  PubMed  CAS  Google Scholar 

  207. Martin, J., Stribbling, S. M., Poon, G. K., Begent, R. H., Napier, M., Sharma, S. K., and Springer, C. J. (1997) Antibody-directed enzyme prodrug therapy: pharmacokinetics and plasma levels of prodrug and drug in a phase I clinical trial. Cancer Chemother Pharmacol 40, 189–201.

    Article  PubMed  CAS  Google Scholar 

  208. Wang, Z., Cook, T., Alber, S., Liu, K., Kovesdi, I., Watkins, S. K., Vodovotz, Y., Billiar, T. R., and Blumberg, D. (2004) Adenoviral gene transfer of the human inducible nitric oxide synthase gene enhances the radiation response of human colorectal cancer associated with alterations in tumor vascularity. Cancer Res 64, 1386–1395.

    Article  PubMed  CAS  Google Scholar 

  209. Griffiths, L., Binley, K., Iqball, S., Kan, O., Maxwell, P., Ratcliffe, P., Lewis, C., Harris, A., Kingsman, S., and Naylor, S. (2000) The macrophage – a novel system to deliver gene therapy to pathological hypoxia. Gene Ther 7, 255–262.

    Article  PubMed  CAS  Google Scholar 

  210. Koshikawa, N., and Takenaga, K. (2005) Hypoxia-regulated expression of attenuated diphtheria toxin A fused with hypoxia-inducible factor-1alpha oxygen-dependent degradation domain preferentially induces apoptosis of hypoxic cells in solid tumor. Cancer Res 65, 11622–11630.

    Article  PubMed  CAS  Google Scholar 

  211. Harada, H., Hiraoka, M., and Kizaka-Kondoh, S. (2002) Antitumor effect of TAT-oxygen-dependent degradation-caspase-3 fusion protein specifically stabilized and activated in hypoxic tumor cells. Cancer Res 62, 2013–2018.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Baylor College of Medicine, Methodist Hospital and Texas Children’s Hospital, Houston, TX, USA

    Danli Wu & Anna May Swanson

Authors
  1. Patricia Yotnda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Danli Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anna May Swanson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Patricia Yotnda .

Editor information

Editors and Affiliations

  1. , Center for Cell and Gene Therapy, Baylor College of Medicine, Baylor Plaza One, Houston, 77030, USA

    Patricia Yotnda

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer Science+Business Media, LLC

About this protocol

Cite this protocol

Yotnda, P., Wu, D., Swanson, A.M. (2010). Hypoxic Tumors and Their Effect on Immune Cells and Cancer Therapy. In: Yotnda, P. (eds) Immunotherapy of Cancer. Methods in Molecular Biology, vol 651. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60761-786-0_1

Download citation

  • DOI: https://doi.org/10.1007/978-1-60761-786-0_1

  • Published:

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-60761-785-3

  • Online ISBN: 978-1-60761-786-0

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation