Cancer Immunology, Immunotherapy

, Volume 56, Issue 11, pp 1687–1700 | Cite as

Dynamic cross-talk between tumor and immune cells in orchestrating the immunosuppressive network at the tumor microenvironment

  • Diego O. Croci
  • Mariano F. Zacarías Fluck
  • María J. Rico
  • Pablo Matar
  • Gabriel A. RabinovichEmail author
  • O. Graciela ScharovskyEmail author


Accumulating evidence indicates that a dynamic cross-talk between tumors and the immune system can regulate tumor growth and metastasis. Increased understanding of the biochemical nature of tumor antigens and the molecular mechanisms responsible for innate and adaptive immune cell activation has revolutionized the fields of tumor immunology and immunotherapy. Both the protective effects of the immune system against tumor cells (immunosurveillance) and the evasion of tumor cells from immune attack (tumor-immune escape) have led to the concept of cancer immunoediting, a proposal which infers that a bidirectional interaction between tumor and inflammatory/regulatory cells is ultimately responsible for orchestrating the immunosuppressive network at the tumor site. In this context, a major challenge is the potentiation or redirection of tumor antigen-specific immune responses. The success in reaching this goal is highly dependent on an improved understanding of the interactions and mechanisms operating during the different phases of the cancer immunoediting process. In this review, we discuss the multiple defense and counterattack strategies that tumors have devised in order to evade immune attack and to thwart the effectiveness of several immunotherapeutic approaches.


Inflammation Immunosuppression Tumor-immune escape Tumor immunoediting 



We would like to give special thanks to Dr. Helene F. Rosenberg (NIAID, NIH, USA) for critical reading of the manuscript. We are also grateful to the members of our laboratories, in particular Marta Toscano, Juan Ilarregui, Germán Bianco and Mariana Salatino for their invaluable help. We apologize that we could not cite many excellent studies because of space limitations. We would like to give special thanks to Fundación Sales (Argentina) for continuous support. Work in the GAR`s laboratories is supported by grants from Cancer Research Institute (Elaine Shepard Investigator Award USA), John Simon Guggenheim Memorial Foundation (USA), Agencia de Promoción Científica y Tecnológica (PICT 2003-05-13787) and University of Buenos Aires (M091, Argentina). Work in O.G.S. laboratory is supported by grants from National University of Rosario (Argentina) and Fundación Sales (Argentina). G.A.R. and P.M are members of the scientific career of the National Research Council (CONICET, Argentina), O.G.S. is a member of the scientific career of the Research Council of the National University of Rosario (CIUNR, Argentina) and D.O.C. is a fellow of the University of Buenos Aires. M.J.R. thanks CONICET and M.F.Z.F. thanks ANPCyT and Fundación SALES for the fellowships granted.


  1. 1.
    Algarra I, Garcia-Lora A, Cabrera T, Ruiz-Cabello F, Garrido F (2004) The selection of tumor variants with altered expression of classical and nonclassical MHC class I molecules: implications for tumor immune escape. Cancer Immunol Immunother 53:904–910PubMedGoogle Scholar
  2. 2.
    Andre S, Pieters RJ, Vrasidas I, Kaltner H, Kuwabara I, Liu FT, Liskamp RM, Gabius HJ (2001) Wedgelike glycodendrimers as inhibitors of binding of mammalian galectins to glycoproteins, lactose maxiclusters, and cell surface glycoconjugates. Chembiochem 2:822–830PubMedGoogle Scholar
  3. 3.
    Andreola G, Rivoltini L, Castelli C, Huber V, Perego P, Deho P, Squarcina P, Accornero P, Lozupone F, Lugini L, Stringaro A, Molinari A, Arancia G, Gentile M, Parmiani G, Fais S (2002) Induction of lymphocyte apoptosis by tumor cell secretion of FasL-bearing microvesicles. J Exp Med 195:1303–1316PubMedGoogle Scholar
  4. 4.
    Bai XF, Liu JQ, Joshi PS, Wang L, Yin L, Labanowska J, Heerema N, Zheng P, Liu Y (2006) Different lineages of P1A-expressing cancer cells use divergent modes of immune evasion for T-cell adoptive therapy. Cancer Res 66:8241–8249PubMedGoogle Scholar
  5. 5.
    Baxevanis CN, Papamichail M (1994) Characterization of the anti-tumor immune response in human cancers and strategies for immunotherapy. Crit Rev Oncol Hematol 16:157–179PubMedGoogle Scholar
  6. 6.
    Bird CH, Sutton VR, Sun J, Hirst CE, Novak A, Kumar S, Trapani JA, Bird PI (1998) Selective regulation of apoptosis: the cytotoxic lymphocyte serpin proteinase inhibitor 9 protects against granzyme B-mediated apoptosis without perturbing the Fas cell death pathway. Mol Cell Biol 18:6387–6398PubMedGoogle Scholar
  7. 7.
    Biswas K, Richmond A, Rayman P, Biswas S, Thornton M, Sa G, Das T, Zhang R, Chahlavi A, Tannenbaum CS, Novick A, Bukowski R, Finke JH (2006) GM2 expression in renal cell carcinoma: potential role in tumor-induced T-cell dysfunction. Cancer Res 66:6816–6825PubMedGoogle Scholar
  8. 8.
    Blank C, Kuball J, Voelkl S, Wiendl H, Becker B, Walter B, Majdic O, Gajewski TF, Theobald M, Andreesen R, Mackensen A (2006) Blockade of PD-L1 (B7-H1) augments human tumor-specific T cell responses in vitro. Int J Cancer 119:317–327PubMedGoogle Scholar
  9. 9.
    Boyland E, Williams DC (1956) The metabolism of tryptophan. 2. The metabolism of tryptophan in patients suffering from cancer of the bladder. Biochem J 64:578–582PubMedGoogle Scholar
  10. 10.
    Bronte V, Serafini P, De Santo C, Marigo I, Tosello V, Mazzoni A, Segal DM, Staib C, Lowel M, Sutter G, Colombo MP, Zanovello P (2003) IL-4-induced arginase 1 suppresses alloreactive T cells in tumor-bearing mice. J Immunol 170:270–278PubMedGoogle Scholar
  11. 11.
    Burnet FM (1970) The concept of immunological surveillance. Prog Exp Tumor Res 13:1–27PubMedGoogle Scholar
  12. 12.
    Cabrera T, Lara E, Romero JM, Maleno I, Real LM, Ruiz-Cabello F, Valero P, Camacho FM, Garrido F (2007) HLA class I expression in metastatic melanoma correlates with tumor development during autologous vaccination. Cancer Immunol Immunother 56:709–717PubMedGoogle Scholar
  13. 13.
    Cresswell AC, Sisley K, Laws D, Parsons MA, Rennie IG, Murray AK (2001) Reduced expression of TAP-1 and TAP-2 in posterior uveal melanoma is associated with progression to metastatic disease. Melanoma Res 11:275–281PubMedGoogle Scholar
  14. 14.
    Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M, Zhu Y, Wei S, Kryczek I, Daniel B, Gordon A, Myers L, Lackner A, Disis ML, Knutson KL, Chen L, Zou W (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10:942–949PubMedGoogle Scholar
  15. 15.
    Curiel TJ, Wei S, Dong H, Alvarez X, Cheng P, Mottram P, Krzysiek R, Knutson KL, Daniel B, Zimmermann MC, David O, Burow M, Gordon A, Dhurandhar N, Myers L, Berggren R, Hemminki A, Alvarez RD, Emilie D, Curiel DT, Chen L, Zou W (2003) Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat Med 9:562–567PubMedGoogle Scholar
  16. 16.
    Chang CC, Ogino T, Mullins DW, Oliver JL, Yamshchikov GV, Bandoh N, Slingluff CL Jr, Ferrone S (2006) Defective human leukocyte antigen class I-associated antigen presentation caused by a novel beta2-microglobulin loss-of-function in melanoma cells. J Biol Chem 281:18763–18773PubMedGoogle Scholar
  17. 17.
    Chen JJ, Sun Y, Nabel GJ (1998) Regulation of the proinflammatory effects of Fas ligand (CD95L). Science 282:1714–1717PubMedGoogle Scholar
  18. 18.
    Cheng J, Zhou T, Liu C, Shapiro JP, Brauer MJ, Kiefer MC, Barr PJ, Mountz JD (1994) Protection from Fas-mediated apoptosis by a soluble form of the Fas molecule. Science 263:1759–1762PubMedGoogle Scholar
  19. 19.
    Chung CD, Patel VP, Moran M, Lewis LA, Miceli MC (2000) Galectin-1 induces partial TCR zeta-chain phosphorylation and antagonizes processive TCR signal transduction. J Immunol 165:3722–3729PubMedGoogle Scholar
  20. 20.
    Dalgleish A, Pandha H (2007) Tumor antigens as surrogate markers and targets for therapy and vaccines. Adv Cancer Res 96:175–190PubMedGoogle Scholar
  21. 21.
    Danguy A, Camby I, Kiss R (2002) Galectins and cancer. Biochim Biophys Acta 1572:285–293PubMedGoogle Scholar
  22. 22.
    Daniel D, Meyer-Morse N, Bergsland EK, Dehne K, Coussens LM, Hanahan D (2003) Immune enhancement of skin carcinogenesis by CD4+ T cells. J Exp Med 197:1017–1028PubMedGoogle Scholar
  23. 23.
    Dannull J, Su Z, Rizzieri D, Yang BK, Coleman D, Yancey D, Zhang A, Dahm P, Chao N, Gilboa E, Vieweg J (2005) Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells. J Clin Invest 115:3623–3633PubMedGoogle Scholar
  24. 24.
    Daroqui CM, Ilarregui JM, Rubinstein N, Salatino M, Toscano MA, Vazquez P, Bakin A, Puricelli L, Bal de Kier Joffe E, Rabinovich GA (2007) Regulation of galectin-1 expression by transforming growth factor beta1 in metastatic mammary adenocarcinoma cells: implications for tumor-immune escape. Cancer Immunol Immunother 56:491–499PubMedGoogle Scholar
  25. 25.
    de Visser KE, Korets LV, Coussens LM (2005) De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. Cancer Cell 7:411–423PubMedGoogle Scholar
  26. 26.
    Demanet C, Mulder A, Deneys V, Worsham MJ, Maes P, Claas FH, Ferrone S (2004) Down-regulation of HLA-A and HLA-Bw6, but not HLA-Bw4, allospecificities in leukemic cells: an escape mechanism from CTL and NK attack? Blood 103:3122–3130PubMedGoogle Scholar
  27. 27.
    Demetriou M, Granovsky M, Quaggin S, Dennis JW (2001) Negative regulation of T-cell activation and autoimmunity by Mgat5 N-glycosylation. Nature 409:733–739PubMedGoogle Scholar
  28. 28.
    Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, Roche PC, Lu J, Zhu G, Tamada K, Lennon VA, Celis E, Chen L (2002) Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 8:793–800PubMedGoogle Scholar
  29. 29.
    Drake CG, Jaffee E, Pardoll DM (2006) Mechanisms of immune evasion by tumors. Adv Immunol 90:51–81PubMedGoogle Scholar
  30. 30.
    Dudley ME, Rosenberg SA (2003) Adoptive-cell-transfer therapy for the treatment of patients with cancer. Nat Rev Cancer 3:666–675PubMedGoogle Scholar
  31. 31.
    Dunn GP, Old LJ, Schreiber RD (2004) The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21:137–148PubMedGoogle Scholar
  32. 32.
    Erlich P (1909) Ueber den jetzigen. Stand der Karzinomforschung Ned Tijdschr Geneeskd 5:273–290Google Scholar
  33. 33.
    Findley HW, Gu L, Yeager AM, Zhou M (1997) Expression and regulation of Bcl-2, Bcl-xl, and Bax correlate with p53 status and sensitivity to apoptosis in childhood acute lymphoblastic leukemia. Blood 89:2986–2993PubMedGoogle Scholar
  34. 34.
    Frydecka I, Kosmaczewska A, Bocko D, Ciszak L, Wolowiec D, Kuliczkowski K, Kochanowska I (2004) Alterations of the expression of T-cell-related costimulatory CD28 and downregulatory CD152 (CTLA-4) molecules in patients with B-cell chronic lymphocytic leukaemia. Br J Cancer 90:2042–2048PubMedGoogle Scholar
  35. 35.
    Fukumori T, Takenaka Y, Yoshii T, Kim HR, Hogan V, Inohara H, Kagawa S, Raz A (2003) CD29 and CD7 mediate galectin-3-induced type II T-cell apoptosis. Cancer Res 63:8302–8311PubMedGoogle Scholar
  36. 36.
    Gabrilovich DI, Chen HL, Girgis KR, Cunningham HT, Meny GM, Nadaf S, Kavanaugh D, Carbone DP (1996) Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells [published erratum appears in Nat Med 1996 Nov;2(11):1267]. Nat Med 2:1096–1103PubMedGoogle Scholar
  37. 37.
    Gabrilovich DI, Velders MP, Sotomayor EM, Kast WM (2001) Mechanism of immune dysfunction in cancer mediated by immature Gr-1+ myeloid cells. J Immunol 166:5398–5406PubMedGoogle Scholar
  38. 38.
    Garcia-Lora A, Algarra I, Garrido F (2003) MHC class I antigens, immune surveillance, and tumor immune escape. J Cell Physiol 195:346–355PubMedGoogle Scholar
  39. 39.
    Garin MI, Chu CC, Golshayan D, Cernuda-Morollon E, Wait R, Lechler RI (2007) Galectin-1: a key effector of regulation mediated by CD4+CD25+ T cells. Blood 109:2058–2065PubMedGoogle Scholar
  40. 40.
    Gastman BR, Johnson DE, Whiteside TL, Rabinowich H (2000) Tumor-induced apoptosis of T lymphocytes: elucidation of intracellular apoptotic events. Blood 95:2015–2023PubMedGoogle Scholar
  41. 41.
    Hahn HP, Pang M, He J, Hernandez JD, Yang RY, Li LY, Wang X, Liu FT, Baum LG (2004) Galectin-1 induces nuclear translocation of endonuclease G in caspase- and cytochrome c-independent T cell death. Cell Death Differ 11:1277–1286PubMedGoogle Scholar
  42. 42.
    Hallermalm K, De Geer A, Kiessling R, Levitsky V, Levitskaya J (2004) Autocrine secretion of Fas ligand shields tumor cells from Fas-mediated killing by cytotoxic lymphocytes. Cancer Res 64:6775–6782PubMedGoogle Scholar
  43. 43.
    Heitger A, Ladisch S (1996) Gangliosides block antigen presentation by human monocytes. Biochim Biophys Acta 1303:161–168PubMedGoogle Scholar
  44. 44.
    Hodi FS, Mihm MC, Soiffer RJ, Haluska FG, Butler M, Seiden MV, Davis T, Henry-Spires R, MacRae S, Willman A, Padera R, Jaklitsch MT, Shankar S, Chen TC, Korman A, Allison JP, Dranoff G (2003) Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci USA 100:4712–4717PubMedGoogle Scholar
  45. 45.
    Igney FH, Behrens CK, Krammer PH (2005) CD95L mediates tumor counterattack in vitro but induces neutrophil-independent tumor rejection in vivo. Int J Cancer 113:78–87PubMedGoogle Scholar
  46. 46.
    Igney FH, Krammer PH (2002) Immune escape of tumors: apoptosis resistance and tumor counterattack. J Leukoc Biol 71:907–920PubMedGoogle Scholar
  47. 47.
    Irmler M, Thome M, Hahne M, Schneider P, Hofmann K, Steiner V, Bodmer JL, Schroter M, Burns K, Mattmann C, Rimoldi D, French LE, Tschopp J (1997) Inhibition of death receptor signals by cellular FLIP. Nature 388:190–195PubMedGoogle Scholar
  48. 48.
    Iwabuchi K, Yamamura S, Prinetti A, Handa K, Hakomori S (1998) GM3-enriched microdomain involved in cell adhesion and signal transduction through carbohydrate-carbohydrate interaction in mouse melanoma B16 cells. J Biol Chem 273:9130–9138PubMedGoogle Scholar
  49. 49.
    Jain R (1993) Physiological resistance to the treatment of solid tumors. In: Teidier BA (ed) Drug resistance in oncology. Dekker New York, pp 87–105Google Scholar
  50. 50.
    Jessup JM, Samara R, Battle P, Laguinge LM (2004) Carcinoembryonic antigen promotes tumor cell survival in liver through an IL-10-dependent pathway. Clin Exp Metastasis 21:709–717PubMedGoogle Scholar
  51. 51.
    Jimenez P, Canton J, Collado A, Cabrera T, Serrano A, Real LM, Garcia A, Ruiz-Cabello F, Garrido F (1999) Chromosome loss is the most frequent mechanism contributing to HLA haplotype loss in human tumors. Int J Cancer 83:91–97PubMedGoogle Scholar
  52. 52.
    Jung EJ, Moon HG, Cho BI, Jeong CY, Joo YT, Lee YJ, Hong SC, Choi SK, Ha WS, Kim JW, Lee CW, Lee JS, Park ST (2007) Galectin-1 expression in cancer-associated stromal cells correlates tumor invasiveness and tumor progression in breast cancer. Int J Cancer 120:2331–2338PubMedGoogle Scholar
  53. 53.
    Kageshita T, Ishihara T, Campoli M, Ferrone S (2005) Selective monomorphic and polymorphic HLA class I antigenic determinant loss in surgically removed melanoma lesions. Tissue Antigens 65:419–428PubMedGoogle Scholar
  54. 54.
    Kidd P (2003) Th1/Th2 balance: the hypothesis, its limitations, and implications for health and disease. Altern Med Rev 8:223–246PubMedGoogle Scholar
  55. 55.
    Kiessling R, Wasserman K, Horiguchi S, Kono K, Sjoberg J, Pisa P, Petersson M (1999) Tumor-induced immune dysfunction. Cancer Immunol Immunother 48:353–362PubMedGoogle Scholar
  56. 56.
    Knutson KL, Disis ML, Salazar LG (2007) CD4 regulatory T cells in human cancer pathogenesis. Cancer Immunol Immunother 56:271–285PubMedGoogle Scholar
  57. 57.
    Kono K, Salazar-Onfray F, Petersson M, Hansson J, Masucci G, Wasserman K, Nakazawa T, Anderson P, Kiessling R (1996) Hydrogen peroxide secreted by tumor-derived macrophages down-modulates signal-transducing zeta molecules and inhibits tumor-specific T cell-and natural killer cell-mediated cytotoxicity. Eur J Immunol 26:1308–1313PubMedGoogle Scholar
  58. 58.
    Korman AJ, Peggs KS, Allison JP (2006) Checkpoint blockade in cancer immunotherapy. Adv Immunol 90:297–339PubMedGoogle Scholar
  59. 59.
    Kortylewski M, Kujawski M, Wang T, Wei S, Zhang S, Pilon-Thomas S, Niu G, Kay H, Mule J, Kerr WG, Jove R, Pardoll D, Yu H (2005) Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat Med 11:1314–1321PubMedGoogle Scholar
  60. 60.
    Krueger A, Baumann S, Krammer PH, Kirchhoff S (2001) FLICE-inhibitory proteins: regulators of death receptor-mediated apoptosis. Mol Cell Biol 21:8247–8254PubMedGoogle Scholar
  61. 61.
    Kryczek I, Zou L, Rodriguez P, Zhu G, Wei S, Mottram P, Brumlik M, Cheng P, Curiel T, Myers L, Lackner A, Alvarez X, Ochoa A, Chen L, Zou W (2006) B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma. J Exp Med 203:871–881PubMedGoogle Scholar
  62. 62.
    Kurnick JT, Ramirez-Montagut T, Boyle LA, Andrews DM, Pandolfi F, Durda PJ, Butera D, Dunn IS, Benson EM, Gobin SJ, van den Elsen PJ (2001) A novel autocrine pathway of tumor escape from immune recognition: melanoma cell lines produce a soluble protein that diminishes expression of the gene encoding the melanocyte lineage melan-A/MART-1 antigen through down-modulation of its promoter. J Immunol 167:1204–1211PubMedGoogle Scholar
  63. 63.
    Kusmartsev S, Gabrilovich DI (2006) Role of immature myeloid cells in mechanisms of immune evasion in cancer. Cancer Immunol Immunother 55:237–45PubMedGoogle Scholar
  64. 64.
    Langowski JL, Zhang X, Wu L, Mattson JD, Chen T, Smith K, Basham B, McClanahan T, Kastelein RA, Oft M (2006) IL-23 promotes tumour incidence and growth. Nature 442:461–465PubMedGoogle Scholar
  65. 65.
    Le QT, Shi G, Cao H, Nelson DW, Wang Y, Chen EY, Zhao S, Kong C, Richardson D, O’Byrne KJ, Giaccia AJ, Koong AC (2005) Galectin-1: a link between tumor hypoxia and tumor immune privilege. J Clin Oncol 23:8932–8941PubMedGoogle Scholar
  66. 66.
    Leach DR, Krummel MF, Allison JP (1996) Enhancement of antitumor immunity by CTLA-4 blockade. Science 271:1734–1736PubMedGoogle Scholar
  67. 67.
    Liu F, Rabinovich G (2005) Galectins as modulators of tumourprogression. Nat Rev Cancer 5(1):29–41PubMedGoogle Scholar
  68. 68.
    Liyanage UK, Moore TT, Joo HG, Tanaka Y, Herrmann V, Doherty G, Drebin JA, Strasberg SM, Eberlein TJ, Goedegebuure PS, Linehan DC (2002) Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol 169:2756–2761PubMedGoogle Scholar
  69. 69.
    Luo JL, Maeda S, Hsu LC, Yagita H, Karin M (2004) Inhibition of NF-kappaB in cancer cells converts inflammation- induced tumor growth mediated by TNFalpha to TRAIL-mediated tumor regression. Cancer Cell 6:297–305PubMedGoogle Scholar
  70. 70.
    Marincola FM, Jaffee EM, Hicklin DJ, Ferrone S (2000) Escape of human solid tumors from T-cell recognition: molecular mechanisms and functional significance. Adv Immunol 74:181–273PubMedGoogle Scholar
  71. 71.
    Matar P, Rozados VR, Gervasoni SI, Scharovsky GO (2002) Th2/Th1 switch induced by a single low dose of cyclophosphamide in a rat metastatic lymphoma model. Cancer Immunol Immunother 50:588–596PubMedGoogle Scholar
  72. 72.
    Matar P, Rozados VR, Gervasoni SI, Scharovsky OG (2001) Down regulation of T-cell-derived IL-10 production by low-dose cyclophosphamide treatment in tumor-bearing rats restores in vitro normal lymphoproliferative response. Int Immunopharmacol 1:307–319PubMedGoogle Scholar
  73. 73.
    Matar P, Rozados VR, Gonzalez AD, Dlugovitzky DG, Bonfil RD, Scharovsky OG (2000) Mechanism of antimetastatic immunopotentiation by low-dose cyclophosphamide. Eur J Cancer 36:1060–1066PubMedGoogle Scholar
  74. 74.
    Matarrese P, Tinari A, Mormone E, Bianco GA, Toscano MA, Ascione B, Rabinovich GA, Malorni W (2004) Galectin-1 sensitizes resting human T lymphocytes to Fas (CD95)-mediated cell death via mitochondrial hyperpolarization, budding and fission. J Biol Chem 280(8):6969–6985PubMedGoogle Scholar
  75. 75.
    Matsuda M, Petersson M, Lenkei R, Taupin JL, Magnusson I, Mellstedt H, Anderson P, Kiessling R (1995) Alterations in the signal-transducing molecules of T cells and NK cells in colorectal tumor-infiltrating, gut mucosal and peripheral lymphocytes: correlation with the stage of the disease. Int J Cancer 61:765–772PubMedGoogle Scholar
  76. 76.
    Medema JP, de Jong J, Peltenburg LT, Verdegaal EM, Gorter A, Bres SA, Franken KL, Hahne M, Albar JP, Melief CJ, Offringa R (2001) Blockade of the granzyme B/perforin pathway through overexpression of the serine protease inhibitor PI-9/SPI-6 constitutes a mechanism for immune escape by tumors. Proc Natl Acad Sci USA 98:11515–11520PubMedGoogle Scholar
  77. 77.
    Miwa K, Asano M, Horai R, Iwakura Y, Nagata S, Suda T (1998) Caspase 1-independent IL-1beta release and inflammation induced by the apoptosis inducer Fas ligand. Nat Med 4:1287–1292PubMedGoogle Scholar
  78. 78.
    Mizoguchi H, O’Shea JJ, Longo DL, Loeffler CM, McVicar DW, Ochoa AC (1992) Alterations in signal transduction molecules in T lymphocytes from tumor-bearing mice. Science 258:1795–1798PubMedGoogle Scholar
  79. 79.
    Mor F, Quintana FJ, Cohen IR (2004) Angiogenesis-inflammation cross-talk: vascular endothelial growth factor is secreted by activated T cells and induces Th1 polarization. J Immunol 172:4618–4623PubMedGoogle Scholar
  80. 80.
    Muller AJ, DuHadaway JB, Donover PS, Sutanto-Ward E, Prendergast GC (2005) Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nat Med 11:312–329PubMedGoogle Scholar
  81. 81.
    Munn DH (2006) Indoleamine 2,3-dioxygenase, tumor-induced tolerance and counter-regulation. Curr Opin Immunol 18:220–225PubMedGoogle Scholar
  82. 82.
    Munn DH, Sharma MD, Hou D, Baban B, Lee JR, Antonia SJ, Messina JL, Chandler P, Koni PA, Mellor AL (2004) Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes. J Clin Invest 114:280–290PubMedGoogle Scholar
  83. 83.
    Murata S, Ladle BH, Kim PS, Lutz ER, Wolpoe ME, Ivie SE, Smith HM, Armstrong TD, Emens LA, Jaffee EM, Reilly RT (2006) OX40 costimulation synergizes with GM-CSF whole-cell vaccination to overcome established CD8+ T cell tolerance to an endogenous tumor antigen. J Immunol 176:974–983PubMedGoogle Scholar
  84. 84.
    Nagata S (1997) Apoptosis by death factor. Cell 88:355–365PubMedGoogle Scholar
  85. 85.
    Nakano Y, Kuroda E, Kito T, Yokota A, Yamashita U (2006) Induction of macrophagic prostaglandin E2 synthesis by glioma cells. J Neurosurg 104:574–582PubMedGoogle Scholar
  86. 86.
    Nakashima M, Sonoda K, Watanabe T (1999) Inhibition of cell growth and induction of apoptotic cell death by the human tumor-associated antigen RCAS1. Nat Med 5:938–942PubMedGoogle Scholar
  87. 87.
    Nefedova Y, Huang M, Kusmartsev S, Bhattacharya R, Cheng P, Salup R, Jove R, Gabrilovich D (2004) Hyperactivation of STAT3 is involved in abnormal differentiation of dendritic cells in cancer. J Immunol 172:464–474PubMedGoogle Scholar
  88. 88.
    North RJ (1982) Cyclophosphamide-facilitated adoptive immunotherapy of an established tumor depends on elimination of tumor-induced suppressor T cells. J Exp Med 155:1063–1074PubMedGoogle Scholar
  89. 89.
    Novellino L, Castelli C, Parmiani G (2005) A listing of human tumor antigens recognized by T cells: March 2004 update. Cancer Immunol Immunother 54:187–207PubMedGoogle Scholar
  90. 90.
    Onizuka S, Tawara I, Shimizu J, Sakaguchi S, Fujita T, Nakayama E (1999) Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. Cancer Res 59:3128–3133PubMedGoogle Scholar
  91. 91.
    Ozaki Y, Edelstein MP, Duch DS (1988) Induction of indoleamine 2,3-dioxygenase: a mechanism of the antitumor activity of interferon gamma. Proc Natl Acad Sci USA 85:1242–1246PubMedGoogle Scholar
  92. 92.
    Paul P, Rouas-Freiss N, Khalil-Daher I, Moreau P, Riteau B, Le Gal FA, Avril MF, Dausset J, Guillet JG, Carosella ED (1998) HLA-G expression in melanoma: a way for tumor cells to escape from immunosurveillance. Proc Natl Acad Sci USA 95:4510–4515PubMedGoogle Scholar
  93. 93.
    Peguet-Navarro J, Sportouch M, Popa I, Berthier O, Schmitt D, Portoukalian J (2003) Gangliosides from human melanoma tumors impair dendritic cell differentiation from monocytes and induce their apoptosis. J Immunol 170:3488–3494PubMedGoogle Scholar
  94. 94.
    Phan GQ, Yang JC, Sherry RM, Hwu P, Topalian SL, Schwartzentruber DJ, Restifo NP, Haworth LR, Seipp CA, Freezer LJ, Morton KE, Mavroukakis SA, Duray PH, Steinberg SM, Allison JP, Davis TA, Rosenberg SA (2003) Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci USA 100:8372–8377PubMedGoogle Scholar
  95. 95.
    Poon RT, Fan ST, Wong J (2001) Clinical implications of circulating angiogenic factors in cancer patients. J Clin Oncol 19:1207–1225PubMedGoogle Scholar
  96. 96.
    Prehn RT, Lappe MA (1971) An immunostimulation theory of tumor development. Transplant Rev 7:26–54PubMedGoogle Scholar
  97. 97.
    Pure E, Allison JP, Schreiber RD (2005) Breaking down the barriers to cancer immunotherapy. Nat Immunol 6:1207–1210PubMedGoogle Scholar
  98. 98.
    Quezada SA, Peggs KS, Curran MA, Allison JP (2006) CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells. J Clin Invest 116:1935–1945PubMedGoogle Scholar
  99. 99.
    Rabinovich GA, Baum LG, Tinari N, Paganelli R, Natoli C, Liu FT, Iacobelli S (2002) Galectins and their ligands: amplifiers, silencers or tuners of the inflammatory response? Trends Immunol 23:313–320PubMedGoogle Scholar
  100. 100.
    Rabinovich GA, Cumashi A, Bianco GA, Ciavardelli D, Iurisci I, D’Egidio M, Piccolo E, Tinari N, Nifantiev N, Iacobelli S (2006) Synthetic lactulose amines: novel class of anticancer agents that induce tumor-cell apoptosis and inhibit galectin-mediated homotypic cell aggregation and endothelial cell morphogenesis. Glycobiology 16:210–220PubMedGoogle Scholar
  101. 101.
    Rabinovich GA, Daly G, Dreja H, Tailor H, Riera CM, Hirabayashi J, Chernajovsky Y (1999) Recombinant galectin-1 and its genetic delivery suppress collagen-induced arthritis via T cell apoptosis. J Exp Med 190:385–398PubMedGoogle Scholar
  102. 102.
    Rabinovich GA, Gabrilovich D, Sotomayor EM (2007) Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol 25:267–296PubMedGoogle Scholar
  103. 103.
    Rabinovich GA, Rubinstein N, Matar P, Rozados V, Gervasoni S, Scharovsky GO (2002) The antimetastatic effect of a single low dose of cyclophosphamide involves modulation of galectin-1 and Bcl-2 expression. Cancer Immunol Immunother 50:597–603PubMedGoogle Scholar
  104. 104.
    Reed JC (2001) The Survivin saga goes in vivo. J Clin Invest 108:965–969PubMedGoogle Scholar
  105. 105.
    Rico MJ, Matar P, Gervasoni SI, Bonfil RD, Calcaterra N, Scharovsky OG (2005) The transition to the metastatic phenotype of rat lymphoma cells involves up-regulation of IL-10 receptor expression and IL-10 secretion. Clin Exp Metastasis 22:127–135PubMedGoogle Scholar
  106. 106.
    Ritter G, Livingston PO (1991) Ganglioside antigens expressed by human cancer cells. Semin Cancer Biol 2:401–409PubMedGoogle Scholar
  107. 107.
    Rivoltini L, Carrabba M, Huber V, Castelli C, Novellino L, Dalerba P, Mortarini R, Arancia G, Anichini A, Fais S, Parmiani G (2002) Immunity to cancer: attack and escape in T lymphocyte-tumor cell interaction. Immunol Rev 188:97–113PubMedGoogle Scholar
  108. 108.
    Rodgers JR, Cook RG (2005) MHC class Ib molecules bridge innate and acquired immunity. Nat Rev Immunol 5:459–471PubMedGoogle Scholar
  109. 109.
    Rodriguez PC, Ochoa AC (2006) T cell dysfunction in cancer: role of myeloid cells and tumor cells regulating amino acid availability and oxidative stress. Semin Cancer Biol 16:66–72PubMedGoogle Scholar
  110. 110.
    Rodriguez T, Mendez R, Roberts CH, Ruiz-Cabello F, Dodi IA, Lopez Nevot MA, Paco L, Maleno I, Marsh SG, Pawelec G, Garrido F (2005) High frequency of homozygosity of the HLA region in melanoma cell lines reveals a pattern compatible with extensive loss of heterozygosity. Cancer Immunol Immunother 54:141–148PubMedGoogle Scholar
  111. 111.
    Romero JM, Jimenez P, Cabrera T, Cozar JM, Pedrinaci S, Tallada M, Garrido F, Ruiz-Cabello F (2005) Coordinated downregulation of the antigen presentation machinery and HLA class I/beta2-microglobulin complex is responsible for HLA-ABC loss in bladder cancer. Int J Cancer 113:605–610PubMedGoogle Scholar
  112. 112.
    Roncarolo MG, Bacchetta R, Bordignon C, Narula S, Levings MK (2001) Type 1 T regulatory cells. Immunol Rev 182:68–79PubMedGoogle Scholar
  113. 113.
    Rosenberg SA (2001) Progress in human tumour immunology and immunotherapy. Nature 411:380–384PubMedGoogle Scholar
  114. 114.
    Rouas-Freiss N, Bruel S, Menier C, Marcou C, Moreau P, Carosella ED (2005) Switch of HLA-G alternative splicing in a melanoma cell line causes loss of HLA-G1 expression and sensitivity to NK lysis. Int J Cancer 117:114–122PubMedGoogle Scholar
  115. 115.
    Rubinstein N, Alvarez M, Zwirner NW, Toscano MA, Ilarregui JM, Bravo A, Mordoh J, Fainboim L, Podhajcer OL, Rabinovich GA (2004) Targeted inhibition of galectin-1 gene expression in tumor cells results in heightened T cell-mediated rejection; a potential mechanism of tumor-immune privilege. Cancer Cell 5:241–251PubMedGoogle Scholar
  116. 116.
    Ryan AE, Shanahan F, O’Connell J, Houston AM (2005) Addressing the “Fas counterattack” controversy: blocking fas ligand expression suppresses tumor immune evasion of colon cancer in vivo. Cancer Res 65:9817–9823PubMedGoogle Scholar
  117. 117.
    Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M (1995) Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155:1151–1164PubMedGoogle Scholar
  118. 118.
    Sanchez-Perez L, Kottke T, Diaz RM, Ahmed A, Thompson J, Chong H, Melcher A, Holmen S, Daniels G, Vile RG (2005) Potent selection of antigen loss variants of B16 melanoma following inflammatory killing of melanocytes in vivo. Cancer Res 65:2009–2017PubMedGoogle Scholar
  119. 119.
    Scaffidi C, Kirchhoff S, Krammer PH, Peter ME (1999) Apoptosis signaling in lymphocytes. Curr Opin Immunol 11:277–285PubMedGoogle Scholar
  120. 120.
    Shimizu J, Yamazaki S, Sakaguchi S (1999) Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol 163:5211–5218PubMedGoogle Scholar
  121. 121.
    Siegel CT, Schreiber K, Meredith SC, Beck-Engeser GB, Lancki DW, Lazarski CA, Fu YX, Rowley DA, Schreiber H (2000) Enhanced growth of primary tumors in cancer-prone mice after immunization against the mutant region of an inherited oncoprotein. J Exp Med 191:1945–1956PubMedGoogle Scholar
  122. 122.
    Sorice M, Parolini I, Sansolini T, Garofalo T, Dolo V, Sargiacomo M, Tai T, Peschle C, Torrisi MR, Pavan A (1997) Evidence for the existence of ganglioside-enriched plasma membrane domains in human peripheral lymphocytes. J Lipid Res 38:969–980PubMedGoogle Scholar
  123. 123.
    Sorme P, Qian Y, Nyholm PG, Leffler H, Nilsson UJ (2002) Low micromolar inhibitors of galectin-3 based on 3′-derivatization of N-acetyllactosamine. Chembiochem 3:183–189PubMedGoogle Scholar
  124. 124.
    Spiotto MT, Rowley DA, Schreiber H (2004) Bystander elimination of antigen loss variants in established tumors. Nat Med 10:294–8PubMedGoogle Scholar
  125. 125.
    Steinman RM, Hawiger D, Nussenzweig MC (2003) Tolerogenic dendritic cells. Annu Rev Immunol 21:685–711PubMedGoogle Scholar
  126. 126.
    Stillman BN, Hsu DK, Pang M, Brewer CF, Johnson P, Liu FT, Baum LG (2006) Galectin-3 and galectin-1 bind distinct cell surface glycoprotein receptors to induce T cell death. J Immunol 176:778–789PubMedGoogle Scholar
  127. 127.
    Strater J, Walczak H, Hasel C, Melzner I, Leithauser F, Moller P (2001) CD95 ligand (CD95L) immunohistochemistry: a critical study on 12 antibodies. Cell Death Differ 8:273–278PubMedGoogle Scholar
  128. 128.
    Sturm A, Lensch M, Andre S, Kaltner H, Wiedenmann B, Rosewicz S, Dignass AU, Gabius HJ (2004) Human galectin-2: novel inducer of T cell apoptosis with distinct profile of caspase activation. J Immunol 173:3825–3837PubMedGoogle Scholar
  129. 129.
    Tanaka M, Suda T, Takahashi T, Nagata S (1995) Expression of the functional soluble form of human fas ligand in activated lymphocytes. Embo J 14:1129–1135PubMedGoogle Scholar
  130. 130.
    Terabe M, Matsui S, Park JM, Mamura M, Noben-Trauth N, Donaldson DD, Chen W, Wahl SM, Ledbetter S, Pratt B, Letterio JJ, Paul WE, Berzofsky JA (2003) Transforming growth factor-beta production and myeloid cells are an effector mechanism through which CD1d-restricted T cells block cytotoxic T lymphocyte-mediated tumor immunosurveillance: abrogation prevents tumor recurrence. J Exp Med 198:1741–1752PubMedGoogle Scholar
  131. 131.
    Thomas L (1982) On immunosurveillance in human cancer. Yale J Biol Med 55:329–333PubMedGoogle Scholar
  132. 132.
    Uyttenhove C, Pilotte L, Theate I, Stroobant V, Colau D, Parmentier N, Boon T, Van den Eynde BJ (2003) Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med 9:1269–1274PubMedGoogle Scholar
  133. 133.
    Uzzo RG, Rayman P, Kolenko V, Clark PE, Cathcart MK, Bloom T, Novick AC, Bukowski RM, Hamilton T, Finke JH (1999) Renal cell carcinoma-derived gangliosides suppress nuclear factor-kappaB activation in T cells. J Clin Invest 104:769–776PubMedGoogle Scholar
  134. 134.
    van der Leij J, van den Berg A, Harms G, Eschbach H, Vos H, Zwiers P, van Weeghel R, Groen H, Poppema S, Visser L (2007) Strongly enhanced IL-10 production using stable galectin-1 homodimers. Mol Immunol 44:506–513PubMedGoogle Scholar
  135. 135.
    van Elsas A, Hurwitz AA, Allison JP (1999) Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation. J Exp Med 190:355–366PubMedGoogle Scholar
  136. 136.
    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 (2004) Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med 10:48–54PubMedGoogle Scholar
  137. 137.
    Weller M, Malipiero U, Aguzzi A, Reed JC, Fontana A (1995) Protooncogene bcl-2 gene transfer abrogates Fas/APO-1 antibody-mediated apoptosis of human malignant glioma cells and confers resistance to chemotherapeutic drugs and therapeutic irradiation. J Clin Invest 95:2633–2643PubMedCrossRefGoogle Scholar
  138. 138.
    Whiteside TL (1999) Signaling defects in T lymphocytes of patients with malignancy. Cancer Immunol Immunother 48:346–352PubMedGoogle Scholar
  139. 139.
    Whiteside TL, Herberman RB (1995) The role of natural killer cells in immune surveillance of cancer. Curr Opin Immunol 7:704–710PubMedGoogle Scholar
  140. 140.
    Wieckowski E, Wang GQ, Gastman BR, Goldstein LA, Rabinowich H (2002) Granzyme B-mediated degradation of T-cell receptor zeta chain. Cancer Res 62:4884–4889PubMedGoogle Scholar
  141. 141.
    Wischhusen J, Friese MA, Mittelbronn M, Meyermann R, Weller M (2005) HLA-E protects glioma cells from NKG2D-mediated immune responses in vitro: implications for immune escape in vivo. J Neuropathol Exp Neurol 64:523–528PubMedGoogle Scholar
  142. 142.
    Yang RY, Hsu DK, Liu FT (1996) Expression of galectin-3 modulates T-cell growth and apoptosis. Proc Natl Acad Sci USA 93:6737–6742PubMedGoogle Scholar
  143. 143.
    Zacarias-Fluck MF, Rico MJ, Gervasoni SI, Ilarregui JM, Toscano MA, Rabinovich GA, Scharovsky GO (2007) Low dose cyclophosphamide modulates galectin-1 expression and function in an experimental rat lymphoma model. Cancer Immunol Immunother 56:237–248PubMedGoogle Scholar
  144. 144.
    Zha Y, Blank C, Gajewski TF (2004) Negative regulation of T-cell function by PD-1. Crit Rev Immunol 24:229–237PubMedGoogle Scholar
  145. 145.
    Zhang X, Huang H, Yuan J, Sun D, Hou WS, Gordon J, Xiang J (2005) CD4–8- dendritic cells prime CD4+ T regulatory 1 cells to suppress antitumor immunity. J Immunol 175:2931–2937PubMedGoogle Scholar
  146. 146.
    Zou W (2005) Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev Cancer 5:263–274PubMedGoogle Scholar
  147. 147.
    Zou W (2006) Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 6:295–307PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Diego O. Croci
    • 1
  • Mariano F. Zacarías Fluck
    • 2
  • María J. Rico
    • 2
  • Pablo Matar
    • 2
  • Gabriel A. Rabinovich
    • 1
    • 3
    Email author
  • O. Graciela Scharovsky
    • 2
    Email author
  1. 1.Institute of Biology and Experimental Medicine IBYME-CONICETBuenos AiresArgentina
  2. 2.Institute of Experimental Genetics, School of Medical SciencesNational University of RosarioRosarioArgentina
  3. 3.Department of Biological Chemistry, FCEyNUniversity of Buenos AiresBuenos AiresArgentina

Personalised recommendations