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Resistance of Cancer Cells to CTL-Mediated Immunotherapy pp 115–142Cite as

Hypoxia: A Formidable Saboteur of the Anti-tumor Response

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Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT,volume 7))

Abstract

The tumor microenvironment (TME) promotes neoplastic transformation, supports tumor growth and invasion, protects the tumor from host immunity and fosters therapeutic resistance. It is well established that tumor stroma components are engaged in an active and complex molecular cross-talk that has serious implications for immunological recognition of tumor cells in shaping the microenvironment. In this regard, a common feature of solid tumors and one of the hallmarks of the TME is at present attracting a particular and increased attention in the field of cancer immunology since hypoxic stress impacts angiogenesis, tumor progression and immune tolerance. In this chapter, we will discuss how tumors use hypoxic stress to their own advantage by activating key biochemical and cellular pathways that are important in their progression and survival and how hypoxic stress induces tumor target adaptation that compromises the effectiveness of CTL activity. In this respect, modulating hypoxia may be a good strategy to control tumor progression at different fronts.

No conflict statement: No potential conflicts of interest were disclosed.

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Abbreviations

CSC:

Cancer stem cells

CTL:

Cytotoxic T lymphocytes

EMT:

Epithelial-to-mesenchymal transition

HIF:

Hypoxia-inducible factor

MDSC:

Myeloid-derived suppressive cells

TAM:

Tumor-associated macrophages

TGF-β:

Transforming growth factor-β

Treg:

T regulatory cells

References

  1. Cormier JN, Salgaller ML, Prevette T, Barracchini KC, Rivoltini L, Restifo NP, Rosenberg SA, Marincola FM. Enhancement of cellular immunity in melanoma patients immunized with a peptide from MART-1/Melan A. Cancer J Sci Am. 1997;3:37–44.

    PubMed Central  CAS  PubMed  Google Scholar 

  2. Jorritsma A, Schumacher TN, Haanen JB. Immunotherapeutic strategies: the melanoma example. Immunotherapy. 2009;1:679–90.

    CAS  PubMed  Google Scholar 

  3. Yasumoto K, Hanagiri T, Takenoyama M. Lung cancer-associated tumor antigens and the present status of immunotherapy against non-small-cell lung cancer. Gen Thorac Cardiovasc Surg. 2009;57:449–57.

    Article  PubMed  Google Scholar 

  4. Chouaib S, Janji B, Tittarelli A, Eggermont A, Thiery JP. Tumor plasticity interferes with anti-tumor immunity. Crit Rev Immunol. 2014;34:91–102.

    Article  CAS  PubMed  Google Scholar 

  5. Laconi E. The evolving concept of tumor microenvironments. Bioessays. 2007;29:738–44.

    Article  CAS  PubMed  Google Scholar 

  6. Harris AL. Hypoxia—a key regulatory factor in tumour growth. Nat Rev Cancer. 2002;2:38–47.

    Article  CAS  PubMed  Google Scholar 

  7. Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005;307:58–62.

    Article  CAS  PubMed  Google Scholar 

  8. Noman MZ, Messai Y, Carre T, Akalay I, Meron M, Janji B, Hasmim M, Chouaib S. Microenvironmental hypoxia orchestrating the cell stroma cross talk, tumor progression and antitumor response. Crit Rev Immunol. 2011;31:357–77.

    Article  CAS  PubMed  Google Scholar 

  9. Facciabene A, Peng X, Hagemann IS, Balint K, Barchetti A, Wang LP, Gimotty PA, Gilks CB, Lal P, Zhang L, Coukos G. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells. Nature. 2011;475:226–30.

    Article  CAS  PubMed  Google Scholar 

  10. Hasmim M, Noman MZ, Messai Y, Bordereaux D, Gros G, Baud V, Chouaib S. Cutting edge: Hypoxia-induced Nanog favors the intratumoral infiltration of regulatory T cells and macrophages via direct regulation of TGF-beta1. J Immunol. 2013;191:5802–6.

    Article  CAS  PubMed  Google Scholar 

  11. Noman MZ, Desantis G, Janji B, Hasmim M, Karray S, Dessen P, Bronte V, Chouaib S. PD-L1 is a novel direct target of HIF-1alpha, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med. 2014;211:781–90.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Keith B, Simon MC. Hypoxia-inducible factors, stem cells, and cancer. Cell. 2007;129:465–72.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Chouaib S, Messai Y, Couve S, Escudier B, Hasmim M, Noman MZ. Hypoxia promotes tumor growth in linking angiogenesis to immune escape. Front Immunol. 2012;3:21.

    Article  PubMed Central  PubMed  Google Scholar 

  14. Ruthenborg RJ, Ban JJ, Wazir A, Takeda N, Kim JW. Regulation of wound healing and fibrosis by hypoxia and hypoxia-inducible factor-1. Mol Cells. 2014;37:637–43.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  15. Shay JE, Celeste SM. Hypoxia-inducible factors: crosstalk between inflammation and metabolism. Semin Cell Dev Biol. 2012;23:389–94.

    Article  CAS  PubMed  Google Scholar 

  16. Semenza GL. Hypoxia-inducible factors in physiology and medicine. Cell. 2012;148:399–408.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH, Gassmann M, Gearhart JD, Lawler AM, Yu AY, Semenza GL. Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. Genes Dev. 1998;12:149–62.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Scholz CC, Taylor CT. Targeting the HIF pathway in inflammation and immunity. Curr Opin Pharmacol. 2013;13:646–53.

    Article  CAS  PubMed  Google Scholar 

  19. Nakamura H, Makino Y, Okamoto K, Poellinger L, Ohnuma K, Morimoto C, Tanaka H. TCR engagement increases hypoxia-inducible factor-1 alpha protein synthesis via rapamycin-sensitive pathway under hypoxic conditions in human peripheral T cells. J Immunol. 2005;174:7592–9.

    Article  CAS  PubMed  Google Scholar 

  20. Lukashev D, Caldwell C, Ohta A, Chen P, Sitkovsky M. Differential regulation of two alternatively spliced isoforms of hypoxia-inducible factor-1 alpha in activated T lymphocytes. J Biol Chem. 2001;276:48754–63.

    Article  CAS  PubMed  Google Scholar 

  21. Makino Y, Nakamura H, Ikeda E, Ohnuma K, Yamauchi K, Yabe Y, Poellinger L, Okada Y, Morimoto C, Tanaka H. Hypoxia-inducible factor regulates survival of antigen receptor-driven T cells. J Immunol. 2003;171:6534–40.

    Article  CAS  PubMed  Google Scholar 

  22. Dang EV, Barbi J, Yang HY, Jinasena D, Yu H, Zheng Y, Bordman Z, Fu J, Kim Y, Yen HR, Luo W, Zeller K, Shimoda L, Topalian SL, Semenza GL, Dang CV, Pardoll DM, Pan F. Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell. 2011;146:772–84.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Ohta A, Diwanji R, Kini R, Subramanian M, Sitkovsky M. In vivo T cell activation in lymphoid tissues is inhibited in the oxygen-poor microenvironment. Front Immunol. 2011;2:27.

    Article  PubMed Central  PubMed  Google Scholar 

  24. Rausch ME, Weisberg S, Vardhana P, Tortoriello DV. Obesity in C57BL/6J mice is characterized by adipose tissue hypoxia and cytotoxic T-cell infiltration. Int J Obes (Lond). 2008;32:451–63.

    Article  CAS  Google Scholar 

  25. Palazon A, Martinez-Forero I, Teijeira A, Morales-Kastresana A, Alfaro C, Sanmamed MF, Perez-Gracia JL, Penuelas I, Hervas-Stubbs S, Rouzaut A, de Landázuri MO, Jure-Kunkel M, Aragonés J, Melero I. The HIF-1alpha hypoxia response in tumor-infiltrating T lymphocytes induces functional CD137 (4-1BB) for immunotherapy. Cancer Discov. 2012;2:608–23.

    Article  CAS  PubMed  Google Scholar 

  26. Caldwell CC, Kojima H, Lukashev D, Armstrong J, Farber M, Apasov SG, Sitkovsky MV. Differential effects of physiologically relevant hypoxic conditions on T lymphocyte development and effector functions. J Immunol. 2001;167:6140–9.

    Article  CAS  PubMed  Google Scholar 

  27. Doedens AL, Phan AT, Stradner MH, Fujimoto JK, Nguyen JV, Yang E, Johnson RS, Goldrath AW. Hypoxia-inducible factors enhance the effector responses of CD8(+) T cells to persistent antigen. Nat Immunol. 2013;14:1173–82.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Finlay DK, Rosenzweig E, Sinclair LV, Feijoo-Carnero C, Hukelmann JL, Rolf J, Panteleyev AA, Okkenhaug K, Cantrell DA. PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+ T cells. J Exp Med. 2012;209:2441–53.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23:549–55.

    Article  CAS  PubMed  Google Scholar 

  30. Lewis JS, Landers RJ, Underwood JC, Harris AL, Lewis CE. Expression of vascular endothelial growth factor by macrophages is up-regulated in poorly vascularized areas of breast carcinomas. J Pathol. 2000;192:150–8.

    Article  CAS  PubMed  Google Scholar 

  31. White JR, Harris RA, Lee SR, Craigon MH, Binley K, Price T, Beard GL, Mundy CR, Naylor S. Genetic amplification of the transcriptional response to hypoxia as a novel means of identifying regulators of angiogenesis. Genomics. 2004;83:1–8.

    Article  CAS  PubMed  Google Scholar 

  32. Werno C, Menrad H, Weigert A, Dehne N, Goerdt S, Schledzewski K, Kzhyshkowska J, Brune B. Knockout of HIF-1alpha in tumor-associated macrophages enhances M2 polarization and attenuates their pro-angiogenic responses. Carcinogenesis. 2010;31:1863–72.

    Article  CAS  PubMed  Google Scholar 

  33. Doedens AL, Stockmann C, Rubinstein MP, Liao D, Zhang N, DeNardo DG, Coussens LM, Karin M, Goldrath AW, Johnson RS. Macrophage expression of hypoxia-inducible factor-1 alpha suppresses T-cell function and promotes tumor progression. Cancer Res. 2010;70:7465–75.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Burke B, Giannoudis A, Corke KP, Gill D, Wells M, Ziegler-Heitbrock L, Lewis CE. Hypoxia-induced gene expression in human macrophages: implications for ischemic tissues and hypoxia-regulated gene therapy. Am J Pathol. 2003;163:1233–43.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Fingleton B, Vargo-Gogola T, Crawford HC, Matrisian LM. Matrilysin [MMP-7] expression selects for cells with reduced sensitivity to apoptosis. Neoplasia. 2001;3:459–68.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009;9:162–74.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Gabrilovich D. Mechanisms and functional significance of tumour-induced dendritic-cell defects. Nat Rev Immunol. 2004;4:941–52.

    Article  CAS  PubMed  Google Scholar 

  38. Serafini P, Mgebroff S, Noonan K, Borrello I. Myeloid-derived suppressor cells promote cross-tolerance in B-cell lymphoma by expanding regulatory T cells. Cancer Res. 2008;68:5439–49.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Corzo CA, Condamine T, Lu L, Cotter MJ, Youn JI, Cheng P, Cho HI, Celis E, Quiceno DG, Padhya T, McCaffrey TV, McCaffrey JC, Gabrilovich DI. HIF-1alpha regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J Exp Med. 2010;207:2439–53.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Trinchieri G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol. 2003;3:133–46.

    Article  CAS  PubMed  Google Scholar 

  41. Clambey ET, McNamee EN, Westrich JA, Glover LE, Campbell EL, Jedlicka P, de Zoeten EF, Cambier JC, Stenmark KR, Colgan SP, Eltzschig HK. Hypoxia-inducible factor-1 alpha-dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa. Proc Natl Acad Sci U S A. 2012;109:E2784–93.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Sitkovsky MV, Kjaergaard J, Lukashev D, Ohta A. Hypoxia-adenosinergic immunosuppression: tumor protection by T regulatory cells and cancerous tissue hypoxia. Clin Cancer Res. 2008;14:5947–52.

    Article  CAS  PubMed  Google Scholar 

  43. Bailey C, Negus R, Morris A, Ziprin P, Goldin R, Allavena P, Peck D, Darzi A. Chemokine expression is associated with the accumulation of tumour associated macrophages (TAMs) and progression in human colorectal cancer. Clin Exp Metastasis. 2007;24:121–30.

    Article  CAS  PubMed  Google Scholar 

  44. Byrne SN, Knox MC, Halliday GM. TGFbeta is responsible for skin tumour infiltration by macrophages enabling the tumours to escape immune destruction. Immunol Cell Biol. 2008;86:92–7.

    Article  CAS  PubMed  Google Scholar 

  45. Yang P, Li QJ, Feng Y, Zhang Y, Markowitz GJ, Ning S, Deng Y, Zhao J, Jiang S, Yuan Y, Wang HY, Cheng SQ, Xie D, Wang XF. TGF-beta-miR-34a-CCL22 signaling-induced Treg cell recruitment promotes venous metastases of HBV-positive hepatocellular carcinoma. Cancer Cell. 2012;22:291–303.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Mauge L, Terme M, Tartour E, Helley D. Control of the adaptive immune response by tumor vasculature. Front Oncol. 2014;4:61.

    Article  PubMed Central  PubMed  Google Scholar 

  47. Engelhardt JJ, Boldajipour B, Beemiller P, Pandurangi P, Sorensen C, Werb Z, Egeblad M, Krummel MF. Marginating dendritic cells of the tumor microenvironment cross-present tumor antigens and stably engage tumor-specific T cells. Cancer Cell. 2012;21:402–17.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Blohm U, Potthoff D, van der Kogel AJ, Pircher H. Solid tumors “melt” from the inside after successful CD8 T cell attack. Eur J Immunol. 2006;36:468–77.

    Article  CAS  PubMed  Google Scholar 

  49. Collet G, Lamerant-Fayel N, Tertil M, El Hafny-Rahbi B, Stepniewski J, Guichard A, Foucault-Collet A, Klimkiewicz K, Petoud S, Matejuk A, Grillon C, Jozkowicz A, Dulak J, Kieda C. Hypoxia-regulated overexpression of soluble VEGFR2 controls angiogenesis and inhibits tumor growth. Mol Cancer Ther. 2014;13:165–78.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Hamzah J, Jugold M, Kiessling F, Rigby P, Manzur M, Manzur M, Marti HH, Rabie T, Kaden S, Gröne HJ, Hämmerling GJ, Arnold B, Ganss R. Vascular normalization in Rgs5-deficient tumours promotes immune destruction. Nature. 2008;453:410–4.

    Article  CAS  PubMed  Google Scholar 

  51. Rolny C, Mazzone M, Tugues S, Laoui D, Johansson I, Coulon C, Squadrito ML, Segura I, Li X, Knevels E, Costa S, Vinckier S, Dresselaer T, Åkerud P, De Mol M, Salomäki H, Phillipson M, Wyns S, Larsson E, Buysschaert I, Botling J, Himmelreich U, Van Ginderachter JA, De Palma M, Dewerchin M, Claesson-Welsh L, Carmeliet P. HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF. Cancer Cell. 2011;19:31–44.

    Article  CAS  PubMed  Google Scholar 

  52. Huang Y, Yuan J, Righi E, Kamoun WS, Ancukiewicz M, Nezivar J, Santosuosso M, Martin JD, Martin MR, Vianello F, Leblanc P, Munn LL, Huang P, Duda DG, Fukumura D, Jain RK, Poznansky MC. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc Natl Acad Sci U S A. 2012;109:17561–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414:105–11.

    Article  CAS  PubMed  Google Scholar 

  54. Pardal R, Clarke MF, Morrison SJ. Applying the principles of stem-cell biology to cancer. Nat Rev Cancer. 2003;3:895–902.

    Article  CAS  PubMed  Google Scholar 

  55. Visvader JE, Lindeman GJ. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer. 2008;8:755–68.

    Article  CAS  PubMed  Google Scholar 

  56. Jogi A, Ora I, Nilsson H, Lindeheim A, Makino Y, Poellinger L, Axelson H, Pahlman S. Hypoxia alters gene expression in human neuroblastoma cells toward an immature and neural crest-like phenotype. Proc Natl Acad Sci U S A. 2002;99:7021–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  57. McCord AM, Jamal M, Shankavaram UT, Lang FF, Camphausen K, Tofilon PJ. Physiologic oxygen concentration enhances the stem-like properties of CD133+ human glioblastoma cells in vitro. Mol Cancer Res. 2009;7:489–97.

    Article  CAS  PubMed  Google Scholar 

  58. Chen Y, De Marco MA, Graziani I, Gazdar AF, Strack PR, Miele L, Bocchetta M. Oxygen concentration determines the biological effects of NOTCH-1 signaling in adenocarcinoma of the lung. Cancer Res. 2007;67:7954–9.

    Article  CAS  PubMed  Google Scholar 

  59. Morrison SJ, Perez SE, Qiao Z, Verdi JM, Hicks C, Weinmaster G, Anderson DJ. Transient Notch activation initiates an irreversible switch from neurogenesis to gliogenesis by neural crest stem cells. Cell. 2000;101:499–510.

    Article  CAS  PubMed  Google Scholar 

  60. Wilson A, Radtke F. Multiple functions of Notch signaling in self-renewing organs and cancer. FEBS Lett. 2006;580:2860–8.

    Article  CAS  PubMed  Google Scholar 

  61. Li Z, Bao S, Wu Q, Wang H, Eyler C, Sathornsumetee S, Shi Q, Cao Y, Lathia J, McLendon RE, Hjelmeland AB, Rich JN. Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell. 2009;15:501–13.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  62. Pietras A, Gisselsson D, Ora I, Noguera R, Beckman S, Navarro S, Pahlman S. High levels of HIF-2alpha highlight an immature neural crest-like neuroblastoma cell cohort located in a perivascular niche. J Pathol. 2008;214:482–8.

    Article  CAS  PubMed  Google Scholar 

  63. Heddleston JM, Li Z, McLendon RE, Hjelmeland AB, Rich JN. The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype. Cell Cycle. 2009;8:3274–84.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  64. Moreno-Manzano V, Rodriguez-Jimenez FJ, Acena-Bonilla JL, Fustero-Lardies S, Erceg S, Dopazo J, Montaner D, Stojkovic M, Sanchez-Puelles JM. FM19G11, a new hypoxia-inducible factor (HIF) modulator, affects stem cell differentiation status. J Biol Chem. 2010;285:1333–42.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  65. Wang Y, Liu Y, Malek SN, Zheng P. Targeting HIF1alpha eliminates cancer stem cells in hematological malignancies. Cell Stem Cell. 2011;8:399–411.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  66. Hasmim M, Noman MZ, Lauriol J, Benlalam H, Mallavialle A, Rosselli F, Mami-Chouaib F, Alcaide-Loridan C, Chouaib S. Hypoxia-dependent inhibition of tumor cell susceptibility to CTL-mediated lysis involves NANOG induction in target cells. J Immunol. 2011;187:4031–9.

    Article  CAS  PubMed  Google Scholar 

  67. Noh KH, Kim BW, Song KH, Cho H, Lee YH, Kim JH, Chung JY, Hewitt SM, Seong SY, Mao CP, Wu TC, Kim TW. Nanog signaling in cancer promotes stem-like phenotype and immune evasion. J Clin Invest. 2012;122:4077–93.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  68. Dobrila-Dintinjana R. Circulating cancer cells are potential weapon for future generations. Hepatogastroenterology. 2014;61:5–8.

    CAS  PubMed  Google Scholar 

  69. Kallergi G, Markomanolaki H, Giannoukaraki V, Papadaki MA, Strati A, Lianidou ES, Georgoulias V, Mavroudis D, Agelaki S. Hypoxia-inducible factor-1alpha and vascular endothelial growth factor expression in circulating tumor cells of breast cancer patients. Breast Cancer Res. 2009;11:R84.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  70. Eliane JP, Repollet M, Luker KE, Brown M, Rae JM, Dontu G, Schott AF, Wicha M, Doyle GV, Hayes DF, Luker GD. Monitoring serial changes in circulating human breast cancer cells in murine xenograft models. Cancer Res. 2008;68:5529–32.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  71. Steinert G, Scholch S, Niemietz T, Iwata N, Garcia SA, Behrens B, Voigt A, Kloor M, Benner A, Bork U, Rahbari NN, Büchler MW, Stoecklein NH, Weitz J. Immune escape and survival mechanisms in circulating tumor cells of colorectal cancer. Cancer Res. 2014;74:1694–704.

    Article  CAS  PubMed  Google Scholar 

  72. Yie SM, Luo B, Ye NY, Xie K, Ye SR. Detection of survivin-expressing circulating cancer cells in the peripheral blood of breast cancer patients by a RT-PCR ELISA. Clin Exp Metastasis. 2006;23:279–89.

    Article  CAS  PubMed  Google Scholar 

  73. Hoffmann AC, Warnecke-Eberz U, Luebke T, Prenzel K, Metzger R, Heitmann M, Neiss S, Vallbohmer D, Hoelscher AH, Schneider PM. Survivin mRNA in peripheral blood is frequently detected and significantly decreased following resection of gastrointestinal cancers. J Surg Oncol. 2007;95:51–4.

    Article  CAS  PubMed  Google Scholar 

  74. Vegran F, Boidot R. Survivin-3B promotes chemoresistance and immune escape by inhibiting caspase-8 and -6 in cancer cells. Oncoimmunology. 2013;2:e26328.

    Article  PubMed Central  PubMed  Google Scholar 

  75. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, Campbell LL, Polyak K, Brisken C, Yang J, Weinberg RA. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133:704–15.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  76. Tsai JH, Donaher JL, Murphy DA, Chau S, Yang J. Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell. 2012;22:725–36.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  77. Kudo-Saito C, Shirako H, Takeuchi T, Kawakami Y. Cancer metastasis is accelerated through immunosuppression during Snail-induced EMT of cancer cells. Cancer Cell. 2009;15:195–206.

    Article  CAS  PubMed  Google Scholar 

  78. Akalay I, Janji B, Hasmim M, Noman MZ, Andre F, De Cremoux P, Bertheau P, Badoual C, Vielh P, Larsen AK, Sabbah M, Tan TZ, Keira JH, Hung NT, Thiery JP, Mami-Chouaib F, Chouaib S. Epithelial-to-mesenchymal transition and autophagy induction in breast carcinoma promote escape from T-cell-mediated lysis. Cancer Res. 2013;73:2418–27.

    Article  CAS  PubMed  Google Scholar 

  79. Akalay I, Tan TZ, Kumar P, Janji B, Mami-Chouaib F, Charpy C, Vielh P, Larsen AK, Thiery JP, Sabbah M, Chouaib S. Targeting WNT1-inducible signaling pathway protein 2 alters human breast cancer cell susceptibility to specific lysis through regulation of KLF-4 and miR-7 expression. Oncogene. 2014;0. doi:10.1038/onc.

  80. Sullivan R, Graham CH. Hypoxia-driven selection of the metastatic phenotype. Cancer Metastasis Rev. 2007;26:319–31.

    Article  CAS  PubMed  Google Scholar 

  81. Volm M, Koomagi R. Hypoxia-inducible factor (HIF-1) and its relationship to apoptosis and proliferation in lung cancer. Anticancer Res. 2000;20:1527–33.

    CAS  PubMed  Google Scholar 

  82. Liu L, Cash TP, Jones RG, Keith B, Thompson CB, Simon MC. Hypoxia-induced energy stress regulates mRNA translation and cell growth. Mol Cell. 2006;21:521–31.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  83. Fink T, Ebbesen P, Koppelhus U, Zachar V. Natural killer cell-mediated basal and interferon-enhanced cytotoxicity against liver cancer cells is significantly impaired under in vivo oxygen conditions. Scand J Immunol. 2003;58:607–12.

    Article  CAS  PubMed  Google Scholar 

  84. Siemens DR, Hu N, Sheikhi AK, Chung E, Frederiksen LJ, Pross H, Graham CH. Hypoxia increases tumor cell shedding of MHC class I chain-related molecule: role of nitric oxide. Cancer Res. 2008;68:4746–53.

    Article  CAS  PubMed  Google Scholar 

  85. Noman MZ, Buart S, Van Pelt J, Richon C, Hasmim M, Leleu N, Suchorska WM, Jalil A, Lecluse Y, El Hage F, Giuliani M, Pichon C, Azzarone B, Mazure N, Romero P, Mami-Chouaib F, Chouaib S. The cooperative induction of hypoxia-inducible factor-1 alpha and STAT3 during hypoxia induced an impairment of tumor susceptibility to CTL-mediated cell lysis. J Immunol. 2009;182:3510–21.

    Article  CAS  PubMed  Google Scholar 

  86. Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C, Darnell Jr JE. Stat3 as an oncogene. Cell. 1999;98:295–303.

    Article  CAS  PubMed  Google Scholar 

  87. Catlett-Falcone R, Landowski TH, Oshiro MM, Turkson J, Levitzki A, Savino R, Ciliberto G, Moscinski L, Fernandez-Luna JL, Nuñez G, Dalton WS, Jove R. Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity. 1999;10:105–15.

    Article  CAS  PubMed  Google Scholar 

  88. Wang T, Niu G, Kortylewski M, Burdelya L, Shain K, Zhang S, Bhattacharya R, Gabrilovich D, Heller R, Coppola D, Dalton W, Jove R, Pardoll D, Yu H. Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med. 2004;10:48–54.

    Article  PubMed  CAS  Google Scholar 

  89. Hussain SF, Kong LY, Jordan J, Conrad C, Madden T, Fokt I, Priebe W, Heimberger AB. A novel small molecule inhibitor of signal transducers and activators of transcription 3 reverses immune tolerance in malignant glioma patients. Cancer Res. 2007;67:9630–6.

    Article  CAS  PubMed  Google Scholar 

  90. Xin H, Zhang C, Herrmann A, Du Y, Figlin R, Yu H. Sunitinib inhibition of Stat3 induces renal cell carcinoma tumor cell apoptosis and reduces immunosuppressive cells. Cancer Res. 2009;69:2506–13.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  91. Ozao-Choy J, Ma G, Kao J, Wang GX, Meseck M, Sung M, Schwartz M, Divino CM, Pan PY, Chen SH. The novel role of tyrosine kinase inhibitor in the reversal of immune suppression and modulation of tumor microenvironment for immune-based cancer therapies. Cancer Res. 2009;69:2514–22.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  92. Chouaib S. Integrating the quality of the cytotoxic response and tumor susceptibility into the design of protective vaccines in tumor immunotherapy. J Clin Invest. 2003;111:595–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  93. Mizushima N. Autophagy: process and function. Genes Dev. 2007;21:2861–73.

    Article  CAS  PubMed  Google Scholar 

  94. Yang Z, Klionsky DJ. Eaten alive: a history of macroautophagy. Nat Cell Biol. 2010;12:814–22.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  95. Mathew R, Karantza-Wadsworth V, White E. Role of autophagy in cancer. Nat Rev Cancer. 2007;7:961–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  96. Corcelle EA, Puustinen P, Jaattela M. Apoptosis and autophagy: Targeting autophagy signalling in cancer cells -‘trick or treats’? FEBS J. 2009;276:6084–96.

    Article  CAS  PubMed  Google Scholar 

  97. Glick D, Barth S, Macleod KF. Autophagy: cellular and molecular mechanisms. J Pathol. 2010;221:3–12.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  98. Yang Z, Klionsky DJ. Mammalian autophagy: core molecular machinery and signaling regulation. Curr Opin Cell Biol. 2010;22:124–31.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  99. Mazure NM, Pouyssegur J. Hypoxia-induced autophagy: cell death or cell survival? Curr Opin Cell Biol. 2010;22:177–80.

    Article  CAS  PubMed  Google Scholar 

  100. Bellot G, Garcia-Medina R, Gounon P, Chiche J, Roux D, Pouyssegur J, Mazure NM. Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains. Mol Cell Biol. 2009;29:2570–81.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  101. Rouschop KM, van den Beucken T, Dubois L, Niessen H, Bussink J, Savelkouls K, Keulers T, Mujcic H, Landuyt W, Voncken JW, Lambin P, van der Kogel AJ, Koritzinsky M, Wouters BG. The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5. J Clin Invest. 2010;120:127–41.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  102. Livesey KM, Tang D, Zeh HJ, Lotze MT. Autophagy inhibition in combination cancer treatment. Curr Opin Investig Drugs. 2009;10:1269–79.

    CAS  PubMed  Google Scholar 

  103. Levine B, Mizushima N, Virgin HW. Autophagy in immunity and inflammation. Nature. 2011;469:323–35.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  104. Chemali M, Radtke K, Desjardins M, English L. Alternative pathways for MHC class I presentation: a new function for autophagy. Cell Mol Life Sci. 2011;68:1533–41.

    Article  CAS  PubMed  Google Scholar 

  105. Crotzer VL, Blum JS. Autophagy and adaptive immunity. Immunology. 2010;131:9–17.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  106. Wightman B, Ha I, Ruvkun G. Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell. 1993;75:855–62.

    Article  CAS  PubMed  Google Scholar 

  107. Alvarez-Garcia I, Miska EA. MicroRNA functions in animal development and human disease. Development. 2005;132:4653–62.

    Article  CAS  PubMed  Google Scholar 

  108. Kulshreshtha R, Davuluri RV, Calin GA, Ivan M. A microRNA component of the hypoxic response. Cell Death Differ. 2008;15:667–71.

    Article  CAS  PubMed  Google Scholar 

  109. Kulshreshtha R, Ferracin M, Wojcik SE, Garzon R, Alder H, Agosto-Perez FJ, Davuluri R, Liu CG, Croce CM, Negrini M, Calin GA, Ivan M. A microRNA signature of hypoxia. Mol Cell Biol. 2007;27:1859–67.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  110. Loscalzo J. The cellular response to hypoxia: tuning the system with microRNAs. J Clin Invest. 2010;120:3815–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  111. Devlin C, Greco S, Martelli F, Ivan M. miR-210. More than a silent player in hypoxia. IUBMB Life. 2011;63:94–100.

    PubMed Central  CAS  PubMed  Google Scholar 

  112. Huang X, Ding L, Bennewith KL, Tong RT, Welford SM, Ang KK, Story M, Le QT, Giaccia AJ. Hypoxia-inducible mir-210 regulates normoxic gene expression involved in tumor initiation. Mol Cell. 2009;35:856–67.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  113. Huang X, Le QT, Giaccia AJ. MiR-210—micromanager of the hypoxia pathway. Trends Mol Med. 2010;16:230–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  114. Camps C, Buffa FM, Colella S, Moore J, Sotiriou C, Sheldon H, Harris AL, Gleadle JM, Ragoussis J. hsa-miR-210 Is induced by hypoxia and is an independent prognostic factor in breast cancer. Clin Cancer Res. 2008;14:1340–8.

    Article  CAS  PubMed  Google Scholar 

  115. Gee HE, Camps C, Buffa FM, Patiar S, Winter SC, Betts G, Homer J, Corbridge R, Cox G, West CM, Ragoussis J, Harris AL. hsa-mir-210 is a marker of tumor hypoxia and a prognostic factor in head and neck cancer. Cancer. 2010;116:2148–58.

    PubMed  Google Scholar 

  116. Pulkkinen K, Malm T, Turunen M, Koistinaho J, Yla-Herttuala S. Hypoxia induces microRNA miR-210 in vitro and in vivo ephrin-A3 and neuronal pentraxin 1 are potentially regulated by miR-210. FEBS Lett. 2008;582:2397–401.

    Article  CAS  PubMed  Google Scholar 

  117. Chouaib S, El Hage F, Benlalam H, Mami-Chouaib F. Immunotherapy of cancer: promise and reality. Med Sci (Paris). 2006;22:755–9 (Article in French).

    Article  Google Scholar 

  118. Dunn GP, Old LJ, Schreiber RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity. 2004;21:137–48.

    Article  CAS  PubMed  Google Scholar 

  119. Patiar S, Harris AL. Role of hypoxia-inducible factor-1alpha as a cancer therapy target. Endocr Relat Cancer. 2006;13 Suppl 1:S61–75.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors are supported by the Ligue contre le Cancer; Institut National du Cancer (INCa); Association de Recherche sur le Cancer (ARC) and INSERM.

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Authors and Affiliations

  1. INSERM U753, Gustave Roussy Campus, 114 rue Edouard Vaillant, 94805, Villejuif, France

    Meriem Hasmim, Yosra Messai, Stéphane Terry, Muhammad Zaeem Noman & Salem Chouaib

  2. Laboratory of Experimental Hemato-Oncology, Centre de Recherche Public de la Santé (CRP-Santé), 84, Val Fleuri, 1526, Luxembourg, Luxembourg

    Bassam Janji

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  1. Meriem Hasmim
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  2. Yosra Messai
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  3. Stéphane Terry
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  4. Bassam Janji
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  5. Muhammad Zaeem Noman
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  6. Salem Chouaib
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Correspondence to Salem Chouaib .

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Editors and Affiliations

  1. Department of Microbiology, Immunology a, University of California at Los Angeles,, Los Angeles, California, USA

    Benjamin Bonavida

  2. Institut Gustave Roussy, Villejuif, France

    Salem Chouaib

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Hasmim, M., Messai, Y., Terry, S., Janji, B., Noman, M.Z., Chouaib, S. (2015). Hypoxia: A Formidable Saboteur of the Anti-tumor Response. In: Bonavida, B., Chouaib, S. (eds) Resistance of Cancer Cells to CTL-Mediated Immunotherapy. Resistance to Targeted Anti-Cancer Therapeutics, vol 7. Springer, Cham. https://doi.org/10.1007/978-3-319-17807-3_6

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