Immune-Mediated Tumor Rejection

  • Ena Wang
  • Francesco M. Marincola


Fundamental strides in the understanding of the molecular basis of tumor rejection were made in the last decade thanks to observational studies performed at relevant time points in human cancerous tissues. The following concepts emerged: immune surveillance against tumors is a likely occurrence. When cancer cells evolve to escape the ongoing immune defense, the neoplastic process reaches a clinically observable phase. By necessity, at this stage, escape mechanisms override anti-cancer mechanisms for tumors to be observable. When cancers become established, two molecular phenotypes can usually be observed: one is characterized by a tumor microenvironment infiltrated by immune cells bearing transcriptional signatures consistent with a status of partial activation. Although incapable of dramatically affecting tumor growth, immune infiltration bears a favorable prognostic and/or predictive connotation on the natural history of the disease or its responsiveness to therapy. In this chapter, we will discuss the significance of transcriptional signatures observed in pre-treatment biopsies as predictive of responsiveness to biological therapy. Moreover, we will discuss the transcriptional signatures observable during and after therapy documenting the switch from chronic to acute inflammation that leads to tumor rejection. We will further discuss how chemotherapy and viral oncolytic therapy, both believed to eliminate tumors exclusively through direct cytotoxicity may play an adjuvant role in stimulating this inflammatory switch. Finally, we will discuss how mechanisms leading to tumor rejection, largely overlap those associated with other aspects of immune-mediated tissue-specific destruction (TSD) such as allograft rejection, graft vs. host disease, acute clearance of pathogen and autoimmunity.


Tumor Microenvironment Allograft Rejection Tumor Rejection Transcriptional Signature Smallpox Vaccine 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Andres A: Cancer incidence after immunosuppressive treatment following kidney transplantation. Crit Rev Oncol Hematol 2005, 56:71–85.PubMedCrossRefGoogle Scholar
  2. Apetoh L, Ghiringhelli F, Tesniere A, Criollo A, Ortiz C, Lidereau R, Mariette C, Chaput N, Mira JP, Delaloge S et al.: The interaction between HMGB1 and TLR4 dictates the outcome of anticancer chemotherapy and radiotherapy. Immunol Rev 2007, 220:47–59.PubMedCrossRefGoogle Scholar
  3. Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, Ortiz C, Criollo A, Mignot G, Maiuri MC, Ullrich E, Saulnier P et al.: Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med 2007, 13:1050–1059.PubMedCrossRefGoogle Scholar
  4. Apetoh L, Tesniere A, Ghiringhelli F, Kroemer G, Zitvogel L: Molecular interactions between dying tumor cells and the innate immune system determine the efficacy of conventional anticancer therapies. Cancer Res 2008, 68:4026–4030.PubMedCrossRefGoogle Scholar
  5. Aptsiauri N, Carretero R, Garcia-Lora A, Real LM, Cabrera T, Garrido F: Regressing and progressing metastatic lesions: resistance to immunotherapy is predetermined by irreversible HLA class I antigen alterations. Cancer Immunol Immunother 2008, 57:1727–1733.PubMedCrossRefGoogle Scholar
  6. Asselah T, Bieche I, Narguet S, Sabbagh A, Laurendeau I, Ripault MP, Boyer N, Martinot-Peignoux M, Valla D, Vidaud M et al.: Liver gene expression signature to predict response to pegylated interferon plus ribavirin combination therapy in patients with chronic hepatitis C. Gut 2008, 57:516–524.PubMedCrossRefGoogle Scholar
  7. Balkwill F, Mantovani A: Inflammation and cancer: back to Virchow? Lancet 2001, 357:539–545.PubMedCrossRefGoogle Scholar
  8. Barry JM, Rosenberg SA: The transformed cell: unlocking the mysteries of cancer. New York, NY: G.P. Putnam’s Sons; 1992.Google Scholar
  9. Benencia F, Courreges MC, Conejo-Garcia JR, Mohamed-Hadley A, Zhang L, Buckanovich RJ, Carroll R, Fraser N, Coukos G: HSV oncolytic therapy upregulates interferon-inducible chemokines and recruits immune effector cells in ovarian cancer. Mol Ther 2005, 12:789–802.PubMedCrossRefGoogle Scholar
  10. Bianchi ME: HMGB1 loves company. J Leukoc Biol 2009, 86:573–576.PubMedCrossRefGoogle Scholar
  11. Bigger CB, Brasky KM, Lanford RE: DNA microarray analysis of chimpanzee liver during acute resolving hepatitis C virus infection. J Virol 2001, 75:7059–7066.PubMedCrossRefGoogle Scholar
  12. Biron CA, Brossay L: NK cells and NKT cells in innate defense against viral infections. Curr Opin Immunol 2001, 13:458–464.PubMedCrossRefGoogle Scholar
  13. Biron CA, Nguyen KB, Pien GC, Cousens LP, Salazar-Mather TP: Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu Rev Immunol 1999, 17:189–220.PubMedCrossRefGoogle Scholar
  14. Brichard VG, Lejeune D: GSK’s antigen-specific cancer immunotherapy programme: pilot results leading to phase III clinical development. Vaccine 2007, 25 Suppl 2:B61–B71.PubMedCrossRefGoogle Scholar
  15. Burnet FM: The concept of immunological surveillance. Prog Exp Tumor Res 1970, 13:1–27.PubMedGoogle Scholar
  16. Callard R, George AJT, Stark J: Cytokines, chaos and complexity. Cell 1999, 11:513.Google Scholar
  17. Camus M, Tosolini M, Mlecnik B, Pages F, Kirilovsky A, Berger A, Costes A, Bindea G, Charoentong P, Bruneval P et al.: Coordination of intratumoral immune reaction and human colorectal cancer recurrence. Cancer Res 2009, 69:2685–2693.PubMedCrossRefGoogle Scholar
  18. Carretero R, Romero JM, Ruiz-Cabello F, Maleno I, Rodriguez F, Camacho FM, Real LM, Garrido F, Cabrera T: Analysis of HLA class I expression in progressing and regressing metastatic melanoma lesions after immunotherapy. Immunogenetics 2008, 60:439–447.PubMedCrossRefGoogle Scholar
  19. Coffey DS: Self-organization, complexity and chaos: the new biology for medicine. Nat Med 1998, 4:882–885.PubMedCrossRefGoogle Scholar
  20. Cormier JN, Hijazi YM, Abati A, Fetsch P, Bettinotti M, Steinberg SM, Rosenberg SA, Marincola FM: Heterogeneous expression of melanoma-associated antigens (MAA) and HLA-A2 in metastatic melanoma in vivo. Int J Cancer 1998, 75:517–524.PubMedCrossRefGoogle Scholar
  21. Costa C, Rufino R, Traves SL, Lapa E, Silva JR, Barnes PJ, Donnelly LE: CXCR3 and CCR5 chemokines in induced sputum from patients with COPD. Chest 2008, 133:26–33.PubMedCrossRefGoogle Scholar
  22. Cucuianu A: Chaos in cancer? Nat Med 1998, 4:1342–1343.PubMedCrossRefGoogle Scholar
  23. Dalgleish A: The relevance of non-linear mathematics (chaos theory) to the treatment of cancer, the role of the immune response and the potential for vaccines. QJM 1999, 92:347–359.PubMedCrossRefGoogle Scholar
  24. Davis SD, Koizumi JH, Pitts WR: Spontaneous regression of pulmonary metastases from renal cell carcinoma. Urology 1989, 33:141–144.PubMedCrossRefGoogle Scholar
  25. Deonarain R, Alcami A, Alexiou M, Dallman MJ, Gewert DR, Porter AC: Impaired antiviral response and alpha/beta interferon induction in mice lacking beta interferon. J Virol 2000, 74:3404–3409.PubMedCrossRefGoogle Scholar
  26. Deonarine K, Panelli MC, Stashower ME, Jin P, Smith K, Slade HB, Norwood C, Wang E, Marincola FM, Stroncek DF: Gene expression profiling of cutaneous wound healing. J Transl Med 2007, 5:11.PubMedCrossRefGoogle Scholar
  27. Dieu-Nosjean MC, Antoine M, Danel C, Heudes D, Wislez M, Poulot V, Rabbe N, Laurans L, Tartour E, de Chaisemartin L et al.: Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures. J Clin Oncol 2008, 26:4410–4417.PubMedCrossRefGoogle Scholar
  28. Dock G: Rabies virus vaccination in a patient with cervical carcinoma. Am J Med Sci 1904, 127:563.Google Scholar
  29. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD: Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 2002, 3:991–998.PubMedCrossRefGoogle Scholar
  30. Dunn GP, Old LJ, Schreiber RD: The immunobiology of cancer immunosurveillance and immunoediting. Immunity 2004, 21:137–148.PubMedCrossRefGoogle Scholar
  31. Farrar MA, Schreiber RD: The molecular cell biology of interferon-gamma and its receptor. Annu Rev Immunol 1993, 11:571–611.PubMedCrossRefGoogle Scholar
  32. Feld JJ, Nanda S, Huang Y, Chen W, Cam M, Pusek SN, Schweigler LM, Theodore D, Zacks SL, Liang TJ et al.: Hepatic gene expression during treatment with peginterferon and ribavirin: identifying molecular pathways for treatment response. Hepatology 2007, 46:1548–1563.PubMedCrossRefGoogle Scholar
  33. Fuchs EJ, Matzinger P: Is cancer dangerous to the immune system? Semin Immunol 1996, 8:271–280.PubMedCrossRefGoogle Scholar
  34. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, Tosolini M, Camus M, Berger A, Wind P et al.: Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 2006, 313:1960–1964.PubMedCrossRefGoogle Scholar
  35. Galon J, Fridman WH, Pages F: The adaptive immunologic microenvironment in colorectal cancer: a novel perspective. Cancer Res 2007, 67:1883–1886.PubMedCrossRefGoogle Scholar
  36. Garcia-Sastre A, Biron CA: Type 1 interferons and the virus-host relationship: a lesson in detente. Science 2006, 312:879–882.PubMedCrossRefGoogle Scholar
  37. Gasser S, Raulet DH: The DNA damage response arouses the immune system. Cancer Res 2006, 66:3959–3962.PubMedCrossRefGoogle Scholar
  38. Ghelani D, Saliba R, Lima M: Secondary malignancies after hematopoietic stem cell transplantation. Crit Rev Oncol Hematol 2005, 56:115–126.PubMedCrossRefGoogle Scholar
  39. Girdlestone J, Isamat M, Gewert D, Milstein C: Transcriptional regulation of HLA-A and -B: differential binding of members of the Rel and IRF families of transcription factors. Proc Natl Acad Sci U S A 1993, 90:11568–11572.PubMedCrossRefGoogle Scholar
  40. Gottschalk S, Heslop HE, Rooney CM: Treatment of Epstein-Barr virus-associated malignancies with specific T cells. Adv Cancer Res 2002, 84:175–201.PubMedCrossRefGoogle Scholar
  41. Green M: Management of Epstein-Barr virus-induced post-tranplant lymphoproliferative disease in recipients of solid organ transplantation. Am J Transplant 2001, 1:103–108.PubMedGoogle Scholar
  42. Hama N, Yanagisawa Y, Dono K, Kobayashi S, Marubashi S, Nagano H, Umeshita K, Watanabe S, Uchiyama Y, Monden M: Gene expression profiling of acute cellular rejection in rat liver transplantation using DNA microarrays. Liver Transpl 2009, 15:509–521.PubMedCrossRefGoogle Scholar
  43. Hao JS, Shan BE: Immune enhancement and anti-tumour activity of IL-23. Cancer Immunol Immunother 2006, 55:1426–1431.PubMedCrossRefGoogle Scholar
  44. Haque T, Taylor C, Wilkie GM, Murad P, Amlot PL, Beath S, McKiernan PJ, Crawford DH: Complete regression of posttransplant lymphoproliferative disease using partially HLA-matched Epstein Barr virus-specific cytotoxic T cells. Transplantation 2001, 72:1399–1402.PubMedCrossRefGoogle Scholar
  45. Hardstedt M, Finnegan CP, Kirchhof N, Hyland KA, Wijkstrom M, Murtaugh MP, Hering BJ: Post-transplant upregulation of chemokine messenger RNA in non-human primate recipients of intraportal pig islet xenografts. Xenotransplantation 2005, 12:293–302.PubMedCrossRefGoogle Scholar
  46. Harlin H, Meng Y, Peterson AC, Zha Y, Tretiakova M, Slingluff C, McKee M, Gajewski TF: Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment. Cancer Res 2009, 69:3077–3085.PubMedCrossRefGoogle Scholar
  47. He XS, Ji X, Hale MB, Cheung R, Ahmed A, Guo Y, Nolan GP, Pfeffer LM, Wright TL, Risch N et al.: Global transcriptional response to interferon is a determinant of HCV treatment outcome and is modified by race. Hepatology 2006, 44:352–359.PubMedCrossRefGoogle Scholar
  48. Heslop HE, Rooney CM: Adoptive cellular immunotherapy for EBV lymphoproliferative disease. Immunol Rev 1997, 157:217–222.PubMedCrossRefGoogle Scholar
  49. Hochhaus A, Yan XH, Willer A, Hehlmann R, Gordon MY, Goldman JM, Melo JV: Expression of interferon regulatory factor (IRF) genes and response to interferon-alpha in chronic myeloid leukemia. Leukemia 1997, 11:933–939.PubMedCrossRefGoogle Scholar
  50. Hu J, Yuan X, Belladonna ML, Ong JM, Wachsmann-Hogiu S, Farkas DL, Black KL, Yu JS: Induction of potent antitumor immunity by intratumoral injection of interleukin 23-transduced dendritic cells. Cancer Res 2006, 66:8887–8896.PubMedCrossRefGoogle Scholar
  51. Huang S, Hendriks W, Althage A, Hemmi S, Bluethmann H, Kamijo R, Vilcek J, Zinkernagel RM, Aguet M: Immune response in mice that lack the interferon-gamma receptor. Science 1993, 259:1742–1745.PubMedCrossRefGoogle Scholar
  52. Imanguli MM, Swaim WD, League SC, Gress RE, Pavletic SZ, Hakim FT: Increased T-bet+ cytotoxic effectors and type I interferon-mediated processes in chronic graft-versus-host disease of the oral mucosa. Blood 2009, 113:3620–3630.PubMedCrossRefGoogle Scholar
  53. Ippoliti G, Rinaldi M, Pellegrini C, Vigano M: Incidence of cancer after immunosuppressive treatment for heart transplantation. Crit Rev Oncol Hematol 2005, 56:101–113.PubMedCrossRefGoogle Scholar
  54. Jacobs N, Chen RA, Gubser C, Najarro P, Smith GL: Intradermal immune response after infection with vaccinia virus. J Gen Virol 2006, 87:1157–1161.PubMedCrossRefGoogle Scholar
  55. Jassar AS, Suzuki E, Kapoor V, Sun J, Silverberg MB, Cheung L, Burdick MD, Strieter RM, Ching LM, Kaiser LR et al.: Activation of tumor-associated macrophages by the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid induces an effective CD8+ T-cell-mediated antitumor immune response in murine models of lung cancer and mesothelioma. Cancer Res 2005, 65:11752–11761.PubMedCrossRefGoogle Scholar
  56. Karason K, Jernas M, Hagg DA, Svensson PA: Evaluation of CXCL9 and CXCL10 as circulating biomarkers of human cardiac allograft rejection. BMC Cardiovasc Disord 2006, 6:29.PubMedCrossRefGoogle Scholar
  57. Karupiah G, Blanden RV, Ramshaw IA: Interferon gamma is involved in the recovery of athymic nude mice from recombinant vaccinia virus/interleukin 2 infection. J Exp Med 1990, 172:1495–1503.PubMedCrossRefGoogle Scholar
  58. Kawakami Y, Robbins P, Wang RF, Parkhurst MR, Kang X, Rosenberg SA: Tumor antigens recognized by T cells. The use of melanosomal proteins in the immunotherapy of melanoma. J Immunother 1998, 21:237–246.PubMedCrossRefGoogle Scholar
  59. Kepp O, Tesniere A, Schlemmer F, Michaud M, Senovilla L, Zitvogel L, Kroemer G: Immunogenic cell death modalities and their impact on cancer treatment. Apoptosis 2009, 14:364–375.PubMedCrossRefGoogle Scholar
  60. Khanna R, Bell S, Sherritt M, Galbraith A, Burrows SR, Rafter L, Clarke B, Slaughter R, Falk MC, Douglass J et al.: Activation and adoptive transfer of Epsten-Barr virus-specific cytotoxic T cells in solid organ transplant patients with posttransplant lymphoproliferative disease. Proc Natl Acad Sci U S A 1999, 96:10391–10396.PubMedCrossRefGoogle Scholar
  61. Kim MJ, Romero R, Kim CJ, Tarca AL, Chhauy S, LaJeunesse C, Lee DC, Draghici S, Gotsch F, Kusanovic JP et al.: Villitis of unknown etiology is associated with a distinct pattern of chemokine up-regulation in the feto-maternal and placental compartments: implications for conjoint maternal allograft rejection and maternal anti-fetal graft-versus-host disease. J Immunol 2009, 182:3919–3927.PubMedCrossRefGoogle Scholar
  62. Langowski JL, Zhang X, Wu L, Mattson JD, Chen T, Smith K, Basham B, McClanahan T, Kastelein RA, Oft M: IL-23 promotes tumour incidence and growth. Nature 2006, 442:461–465.PubMedCrossRefGoogle Scholar
  63. Lee K-H, Panelli MC, Kim CJ, Riker A, Roden M, Fetsch PA, Abati A, Bettinotti MP, Rosenberg SA, Marincola FM: Functional dissociation between local and systemic immune response following peptide vaccination. J Immunol 1998, 161:4183–4194.PubMedGoogle Scholar
  64. Lokich J: Spontaneous regression of metastatic renal cancer. Case report and literature review. Am J Clin Oncol 1997, 20:416–418.PubMedCrossRefGoogle Scholar
  65. Lucas M, Schachterle W, Oberle K, Aichele P, Diefenbach A: Dendritic cells prime natural killer cells by trans-presenting interleukin 15. Immunity 2007, 26:503–517.PubMedCrossRefGoogle Scholar
  66. Mandruzzato S, Callegaro A, Turcatel G, Francescato S, Montesco MC, Chiarion-Sileni V, Mocellin S, Rossi CR, Bicciato S, Wang E et al.: A gene expression signature associated with survival in metastatic melanoma. J Transl Med 2006, 4:50.PubMedCrossRefGoogle Scholar
  67. Mantovani A: Cancer: inflammation by remote control. Nature 2005, 435:752–753.PubMedCrossRefGoogle Scholar
  68. Mantovani A, Gray PA, Van Damme J, Sozzani S: Macrophage-derived chemokine (MDC). J Leukoc Biol 2000, 68:400–404.PubMedGoogle Scholar
  69. Mantovani A, Sozzani S, Locati M, Allavena P, Sica A: Macrophage polarization: tumor-associated macrophage as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 2002, 23:549–555.PubMedCrossRefGoogle Scholar
  70. Mantovani A, Romero P, Palucka AK, Marincola FM: Tumor immunity: effector response to tumor and the influence of the microenvironment. Lancet 2008, 371:771–783.PubMedCrossRefGoogle Scholar
  71. Marincola FM, Jaffe EM, Hicklin DJ, Ferrone S: Escape of human solid tumors from T cell recognition: molecular mechanisms and functional significance. Adv Immunol 2000, 74:181–273.PubMedCrossRefGoogle Scholar
  72. Marincola FM, Wang E, Herlyn M, Seliger B, Ferrone S: Tumors as elusive targets of T cell-based active immunotherapy. Trends Immunol 2003, 24:335–342.PubMedCrossRefGoogle Scholar
  73. Martin DN, Boersma BJ, Yi M, Reimers M, Howe TM, Yfantis HG, Tsai YC, Williams EH, Lee DH, Stephens RM et al.: Differences in the tumor microenvironment between African-American and European-American breast cancer patients. PLoS ONE 2009, 4:e4531.PubMedCrossRefGoogle Scholar
  74. Martinez J, Huang X, Yang Y: Direct action of type I IFN on NK cells is required for their activation in response to vaccinia viral infection in vivo. J Immunol 2008, 180:1592–1597.PubMedGoogle Scholar
  75. Mocellin S, Nitti D: Therapeutics targeting tumor immune escape: towards the development of new generation anticancer vaccines. Med Res Rev 2007, 28(3):413–414, 2008.Google Scholar
  76. Mocellin S, Panelli MC, Wang E, Nagorsen D, Marincola FM: The dual role of IL-10. Trends Immunol 2002, 24:36–43.CrossRefGoogle Scholar
  77. Monsurro’ V, Beghelli S, Wang R, Barbi S, Coin S, Di Pasquale G, Bersani S, Castellucci M, Sorio C, Eleuteri S et al.: Anti-viral status segregates two pancreatic adenocarcinoma molecular phenotypes with potential relevance for adenoviral gene therapy. J Transl Med 2009, 8:10, 2010.Google Scholar
  78. Nanda S, Havert MB, Calderon GM, Thomson M, Jacobson C, Kastner D, Liang TJ: Hepatic transcriptome analysis of hepatitis C virus infection in chimpanzees defines unique gene expression patterns associated with viral clearance. PLoS ONE 2008, 3:e3442.PubMedCrossRefGoogle Scholar
  79. Ogasawara K, Hida S, Azimi N, Tagaya Y, Sato T, Yokochi-Fukuda T, Waldmann TA, Taniguchi T, Taki S: Requirement for IRF-1 in the microenvironment supporting development of natural killer cells. Nature 1998, 391:700–703.PubMedCrossRefGoogle Scholar
  80. Ohnmacht GA, Wang E, Mocellin S, Abati A, Filie A, Fetsch PA, Riker A, Kammula US, Rosenberg SA, Marincola FM: Short term kinetics of tumor antigen expression in response to vaccination. J Immunol 2001, 167:1809–1820.PubMedGoogle Scholar
  81. Okamoto Y, Folco EJ, Minami M, Wara AK, Feinberg MW, Sukhova GK, Colvin RA, Kihara S, Funahashi T, Luster AD et al.: Adiponectin inhibits the production of CXC receptor 3 chemokine ligands in macrophages and reduces T-lymphocyte recruitment in atherogenesis. Circ Res 2008, 102:218–225.PubMedCrossRefGoogle Scholar
  82. Oniki S, Nagai H, Horikawa T, Furukawa J, Belladonna ML, Yoshimoto T, Hara I, Nishigori C: Interleukin-23 and interleukin-27 exert quite different antitumor and vaccine effects on poorly immunogenic melanoma. Cancer Res 2006, 66:6395–6404.PubMedCrossRefGoogle Scholar
  83. Overwijk WW, De Visser KE, Tirion FH, de Jong LA, Pols TW, van der Velden YU, van den Boorn JG, Keller AM, Buurman WA, Theoret MR et al.: Immunological and antitumor effects of IL-23 as a cancer vaccine adjuvant. J Immunol 2006, 176:5213–5222.PubMedGoogle Scholar
  84. Pages F, Berger A, Camus M, Sanchez-Cabo F, Costes A, Molidor R, Mlecnik B, Kirilovsky A, Nilsson M, Damotte D et al.: Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 2005, 353:2654–2666.PubMedCrossRefGoogle Scholar
  85. Pages F, Kirilovsky A, Mlecnik B, Asslaber M, Tosolini M, Bindea G, Lagorce C, Wind P, Bruneval P, Zatloukal K et al.: The in situ cytotoxic and memory T cells predict outcome in early-stage colerectal cancer patients. J Clin Oncol 2009, 27(35):5944–5951.PubMedCrossRefGoogle Scholar
  86. Pages F, Galon J, Dieu-Nosjean MC, Tartour E, Sautes-Fridman C, Fridman WH: Immune infiltration in human tumors, a prognostic factor that should not be ignored. Oncogene 2010, 29(8):1093–1102.PubMedCrossRefGoogle Scholar
  87. Panelli MC, Wang E, Phan G, Puhlman M, Miller L, Ohnmacht GA, Klein H, Marincola FM: Gene-expression profiling of the response of peripheral blood mononuclear cells and melanoma metastases to systemic IL-2 administration. Genome Biol 2002, 3:RESEARCH0035.Google Scholar
  88. Panelli MC, Martin B, Nagorsen D, Wang E, Smith K, Monsurro’ V, Marincola FM: A genomic and proteomic-based hypothesis on the eclectic effects of systemic interleukin-2 administration in the context of melanoma-specific immunization. Cells Tissues Organs 2003, 177:124–131.CrossRefGoogle Scholar
  89. Panelli MC, White RL Jr., Foster M, Martin B, Wang E, Smith K, Marincola FM: Forecasting the cytokine storm following systemic interleukin-2 administration. J Transl Med 2004, 2:17.PubMedCrossRefGoogle Scholar
  90. Panelli MC, Stashower M, Slade HB, Smith K, Norwood C, Abati A, Fetsch PA, Filie A, Walters SA, Astry C et al.: Sequential gene profiling of basal cell carcinomas treated with Imiquimod in a placebo-controlled study defines the requirements for tissue rejection. Genome Biol 2006, 8:R8.CrossRefGoogle Scholar
  91. Parato KA, Senger D, Forsyth PA, Bell JC: Recent progress in the battle between oncolytic viruses and tumours. Nat Rev Cancer 2005, 5:965–976.PubMedCrossRefGoogle Scholar
  92. Paun A, Pitha PM: The IRF family, revisited. Biochimie 2007, 89:744–753.PubMedCrossRefGoogle Scholar
  93. Reading PC, Smith GL: A kinetic analysis of immune mediators in the lungs of mice infected with vaccinia virus and comparison with intradermal infection. J Gen Virol 2003, 84:1973–1983.PubMedCrossRefGoogle Scholar
  94. Reeve J, Einecke G, Mengel M, Sis B, Kayser N, Kaplan B, Halloran PF: Diagnosing rejection in renal transplants: a comparison of molecular- and histopathology-based approaches. Am J Transplant 2009, 9:1802–1810.PubMedCrossRefGoogle Scholar
  95. Rehermann B, Nascimbeni M: Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol 2005, 5:215–229.PubMedCrossRefGoogle Scholar
  96. Reits EA, Hodge JW, Herberts CA, Groothuis TA, Chakraborty M, Wansley EK, Camphausen K, Luiten RM, de Ru AH, Neijssen J et al.: Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J Exp Med 2006, 203:1259–1271.PubMedCrossRefGoogle Scholar
  97. Rew DA: Tumour biology, chaos and non-linear dynamics. Eur J Surg Oncol 1999, 25:86–89.PubMedCrossRefGoogle Scholar
  98. Robbins PF, el-Gamil M, Li YF, Kawakami Y, Loftus D, Appella E, Rosenberg SA: A mutated beta-catenin gene encodes a melanoma-specific antigen recognized by tumor infiltrating lymphocytes. J Exp Med 1996, 183:1185–1192.PubMedCrossRefGoogle Scholar
  99. Roberts ZJ, Goutagny N, Perera PY, Kato H, Kumar H, Kawai T, Akira S, Savan R, van Echo D, Fitzgerald KA et al.: The chemotherapeutic agent DMXAA potently and specifically activates the TBK1-IRF-3 signaling axis. J Exp Med 2007, 204:1559–1569.PubMedCrossRefGoogle Scholar
  100. Rooney CM, Roskrow MA, Smith CA, Brenner MK, Heslop HE: Immunotherapy of Epstein-Barr virus-associated cancer. J Natl Cancer Inst Monogr 1998, 23:89–93.PubMedCrossRefGoogle Scholar
  101. Saint-Mezard P, Berthier CC, Zhang H, Hertig A, Kaiser S, Schumacher M, Wieczorek G, Bigaud M, Kehren J, Rondeau E et al.: Analysis of independent microarray datasets of renal biopsies identifies a robust transcript signature of acute allograft rejection. Transpl Int 2009, 22:293–302.PubMedCrossRefGoogle Scholar
  102. Salk J: Immunological paradoxes: theoretical considerations in the rejection or retention of grafts, tumors, and normal tissue. Ann N Y Acad Sci 1969, 164:365–380.PubMedCrossRefGoogle Scholar
  103. Sanchez-Ortiz RF, Tannir N, Ahrar K, Wood CG: Spontaneous regression of pulmonary metastases from renal cell carcinoma after radio frequency ablation of primary tumor: an in situ tumor vaccine? J Urol 2003, 170:178–179.PubMedCrossRefGoogle Scholar
  104. Sarwal M, Chua MS, Kambham N, Hsieh SC, Satterwhite T, Masek M, Salvatierra O, Jr.: Molecular heterogeneity in acute renal allograft rejection identified by DNA microarray profiling. N Engl J Med 2003, 349:125–138.PubMedCrossRefGoogle Scholar
  105. Schellekens H, de Reus A, Bolhuis R, Fountoulakis M, Schein C, Ecsodi J, Nagata S, Weissmann C: Comparative antiviral efficiency of leukocyte and bacterially produced human alpha-interferon in rhesus monkeys. Nature 1981, 292:775-776PubMedCrossRefGoogle Scholar
  106. Selin LK, Santolucito PA, Pinto AK, Szomolanyi-Tsuda E, Welsh RM: Innate immunity to viruses: control of vaccinia virus infection by gamma delta T cells. J Immunol 2001, 166:6784–6794.PubMedGoogle Scholar
  107. Shan BE, Hao JS, Li QX, Tagawa M: Antitumor activity and immune enhancement of murine interleukin-23 expressed in murine colon carcinoma cells. Cell Mol Immunol 2006, 3:47–52.PubMedGoogle Scholar
  108. Shankaran V, Ikeda H, Bruce AT, White JM, Swanson PE, Old LJ, Schreiber RD: IFN-γ and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 2001, 410:1107–1111.PubMedCrossRefGoogle Scholar
  109. Shanker A, Verdeil G, Buferne M, Inderberg-Suso EM, Puthier D, Joly F, Nguyen C, Leserman L, Auphan-Anezin N, Schmitt-Verhulst AM: CD8 T cell help for innate antitumor immunity. J Immunol 2007, 179:6651–6662.PubMedGoogle Scholar
  110. Sinkovics J, Horvath J: New developments in the virus therapy of cancer: a historical review. Intervirology 1993, 36:193–214.PubMedGoogle Scholar
  111. Srikrishna G, Freeze HH: Endogenous damage-associated molecular pattern molecules at the crossroads of inflammation and cancer. Neoplasia 2009, 11:615–628.PubMedGoogle Scholar
  112. Tahara H, Sato M, Thurin M, Wang E, Butterfield LH, Disis ML, Fox BA, Lee PP, Khleif SN, Wigginton JM et al.: Emerging concepts in biomarker discovery; the US-Japan workshop on immunological molecular markers in oncology. J Transl Med 2009, 7:45.PubMedCrossRefGoogle Scholar
  113. Taieb J, Chaput N, Menard C, Apetoh L, Ullrich E, Bonmort M, Pequignot M, Casares N, Terme M, Flament C et al.: A novel dendritic cell subset involved in tumor immunosurveillance. Nat Med 2006, 12:214–219.PubMedCrossRefGoogle Scholar
  114. Taniguchi T: Transcription factors IRF-1 and IRF-2: linking the immune responses and tumor suppression. J Cell Physiol 1997, 173:128–130.PubMedCrossRefGoogle Scholar
  115. Taylor AL, Marcus R, Bradley JA: Post-transplant lymphoproliferative disorders (PTLD) after solid organ transplantation. Crit Rev Oncol Hematol 2005, 56:155–167.PubMedCrossRefGoogle Scholar
  116. Tesniere A, Apetoh L, Ghiringhelli F, Joza N, Panaretakis T, Kepp O, Schlemmer F, Zitvogel L, Kroemer G: Immunogenic cancer cell death: a key-lock paradigm. Curr Opin Immunol 2008, 20(5):504–511.PubMedCrossRefGoogle Scholar
  117. Tesniere A, Schlemmer F, Boige V, Kepp O, Martins I, Ghiringhelli F, Aymeric L, Michaud M, Apetoh L, Barault L et al.: Immunogenic death of colon cancer cells treated with oxaliplatin. Oncogene 2010, 29(4):482–491.PubMedCrossRefGoogle Scholar
  118. Vaha-Koskela MJ, Heikkila JE, Hinkkanen AE: Oncolytic viruses in cancer therapy. Cancer Lett 2007, 254:178–216.PubMedCrossRefGoogle Scholar
  119. Vallejo GH, Romero CJ, de Vicente JC: Incidence and risk factors for cancer after liver transplantation. Crit Rev Oncol Hematol 2005, 56:87–99.PubMedCrossRefGoogle Scholar
  120. Wallace TA, Prueitt RL, Yi M, Howe TM, Gillespie JW, Yfantis HG, Stephens RM, Caporaso NE, Loffredo CA, Ambs S: Tumor immunobiological differences in prostate cancer between African-American and European-American men. Cancer Res 2008, 68:927–936.PubMedCrossRefGoogle Scholar
  121. Wang E: RNA amplification for successful gene profiling analysis. J Transl Med 2005, 3:28.PubMedCrossRefGoogle Scholar
  122. Wang E, Marincola FM: A natural history of melanoma: serial gene expression analysis. Immunol Today 2000, 21:619–623.PubMedCrossRefGoogle Scholar
  123. Wang E, Marincola FM: Amplification of small quantities of mRNA for transcript analysis. In DNA arrays – a molecular cloning manual. First edition. Edited by Bowtell D, Sambrook J. Cold Springs Harbor, NY: Cold Spring Harbor Laboratory Press; 2002:204–213.Google Scholar
  124. Wang E, Marincola FM: Bottom up: a modular view of immunology. Immunity 2008, 29:9–11.PubMedCrossRefGoogle Scholar
  125. Wang E, Miller L, Ohnmacht GA, Liu E, Marincola FM: High fidelity mRNA amplification for gene profiling using cDNA microarrays. Nat Biotechnol 2000, 17:457–459.Google Scholar
  126. Wang E, Miller LD, Ohnmacht GA, Mocellin S, Petersen D, Zhao Y, Simon R, Powell JI, Asaki E, Alexander HR et al.: Prospective molecular profiling of subcutaneous melanoma metastases suggests classifiers of immune responsiveness. Cancer Res 2002, 62:3581–3586.PubMedGoogle Scholar
  127. Wang E, Panelli MC, Monsurro’ V, Marincola FM: Gene expression profiling of anti-cancer immune responses. Curr Opin Mol Ther 2004, 6:288–295.PubMedGoogle Scholar
  128. Wang E, Panelli MC, Marincola FM: Gene profiling of immune responses against tumors. Curr Opin Immunol 2005, 17:423–427.PubMedCrossRefGoogle Scholar
  129. Wang E, Panelli M, Marincola FM: Autologous tumor rejection in humans: trimming the myths. Immunol Invest 2006, 35:437–458.PubMedCrossRefGoogle Scholar
  130. Wang E, Selleri S, Sabatino M, Monaco A, Pos Z, Stroncek DF, Marincola FM: Spontaneous and tumor-induced cancer rejection in humans. Expert Opin Biol Ther 2008, 8:337–349.PubMedCrossRefGoogle Scholar
  131. Wang E, Worschech A, Marincola FM: The immunologic constant of rejection. Trends Immunol 2008, 29:256–262.PubMedCrossRefGoogle Scholar
  132. Wang E, Albini A, Stroncek DF, Marincola FM: New take on comparative immunology: relevance to immunotherapy. Immunotherapy 2009, 1:355–366.PubMedCrossRefGoogle Scholar
  133. Worschech A, Chen N, Yu YA, Zhang Q, Pos Z, Weibel S, Raab V, Sabatino M, Monaco A, Liu H et al.: Systemic treatment of xenografts with vaccinia virus GLV-1h68 reveals the immunologic facets of oncolytic therapy. BMC Genomics 2009, 10:301.PubMedCrossRefGoogle Scholar
  134. Worschech A, Haddad D, Stroncek DF, Wang E, Marincola FM, Szalay AA: The immunologic aspects of poxvirus oncolytic therapy. Cancer Immunol Immunother 2009, 58(9):1355–1362.PubMedCrossRefGoogle Scholar
  135. Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, Makrigiannakis A, Gray H, Schlienger K, Liebman MN et al.: Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 2003, 348:203–213.PubMedCrossRefGoogle Scholar
  136. Zhang Q, Yu YA, Wang E, Chen N, Danner RL, Munson PJ, Marincola FM, Szalay AA: Eradication of solid human breast tumors in nude mice with an intravenously injected light-emitting oncolytic vaccinia virus. Cancer Res 2007, 67:10038–10046.PubMedCrossRefGoogle Scholar
  137. Zhao DX, Hu Y, Miller GG, Luster AD, Mitchell RN, Libby P: Differential expression of the IFN-gamma-inducible CXCR3-binding chemokines, IFN-inducible protein 10, monokine induced by IFN, and IFN-inducible T cell alpha chemoattractant in human cardiac allografts: association with cardiac allograft vasculopathy and acute rejection. J Immunol 2002, 169:1556–1560.PubMedGoogle Scholar
  138. Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G: Immunological aspects of cancer chemotherapy. Nat Rev Immunol 2008, 8:59–73.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center and Trans-NIH Center for Human Immunology (CHI)National institutes of HealthBethesdaUSA

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