Cancer Immunology, Immunotherapy

, Volume 56, Issue 2, pp 227–236 | Cite as

Immune selective pressure and HLA class I antigen defects in malignant lesions

  • Chien-Chung Chang
  • Soldano FerroneEmail author
Original Article


The revived cancer immune surveillance theory has emphasized the active role the immune system plays in eliminating tumor cells and in facilitating the emergence of their immunoresistant variants. MHC class I molecule abnormalities represent, at least in part, the molecular phenotype of these escape variants, given the crucial role of MHC class I molecules in eliciting tumor antigen-specific T cell responses, the high frequency of HLA class I antigen abnormalities in malignant lesions and their association with a poor clinical course of the disease. Here, we present evidence for this possibility and review the potential mechanisms by which T cell selective pressure participates in the generation of tumor cells with MHC class I molecule defects. Furthermore, we discuss the strategies to counteract tumor cell immune evasion.


Darwin theory Immune surveillance Immune selection Immunoprevention Immunotherapy Malignant disease MHC class I antigens 



This work was supported by PHS grants R01 CA67108, R01 CA110249 and R01 CA113861 awarded by the National Cancer Institute, DHHS.


  1. 1.
    Reisfeld RA, Sevier DE, Pellegrino MA, Ferrone S, Poulik MD (1975) Association of HL-A antigens and β2-microglobulin at the cellular and molecular level. Immunogenetics 2:183CrossRefGoogle Scholar
  2. 2.
    Welsh KI, Dorval G, Nilsson K, Clements GB, Wigzell H (1977) Quantitation of β2-microglobulin and HLA on the surface of human cells. II. In vitro cell lines and their hybrids. Scand J Immunol 6:265PubMedCrossRefGoogle Scholar
  3. 3.
    Jones EA, Bodmer WF (1980) Lack of expression of HLA antigens on choriocarcinoma cell lines. Tissue Antigens 16:195PubMedCrossRefGoogle Scholar
  4. 4.
    Holden CA, Sanderson AR, MacDonald DM (1983) Absence of human leukocyte antigen molecules in skin tumors and some cutaneous appendages: evidence using monoclonal antibodies. J Am Acad Dermatol 9:867PubMedCrossRefGoogle Scholar
  5. 5.
    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 74:181PubMedCrossRefGoogle Scholar
  6. 6.
    Dudley ME, Wunderlich JR, Robbins PF, Yang JC, Hwu P, Schwartzentruber DJ, Topalian SL, Sherry R, Restifo NP, Hubicki AM, Robinson MR, Raffeld M, Duray P, Seipp CA, Rogers-Freezer L, Morton KE, Mavroukakis SA, White DE, Rosenberg SA (2002) Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298:85CrossRefGoogle Scholar
  7. 7.
    Yee C, Thompson JA, Byrd D, Riddell SR, Roche P, Celis E, Greenberg PD (2002) Adoptive T cell therapy using antigen-specific CD8+ T cell clones for the treatment of patients with metastatic melanoma: in vivo persistence, migration, and antitumor effect of transferred T cells. Proc Natl Acad Sci USA 99:16168PubMedCrossRefGoogle Scholar
  8. 8.
    Schreiber H (2003) Tumor immunology. In: Paul ED (ed) Fundamental Immunology. Lippincott Williams and Wilkins, Philadephia, pp 1557Google Scholar
  9. 9.
    Wolfel T, Klehmann E, Muller C, Schutt KH, Meyer zum Buschenfelde KH, Knuth A (1989) Lysis of human melanoma cells by autologous cytolytic T cell clones. Identification of human histocompatibility leukocyte antigen A2 as a restriction element for three different antigens. J Exp Med 170:797PubMedCrossRefGoogle Scholar
  10. 10.
    Crowley NJ, Darrow TL, Quinn-Allen MA, Seigler HF (1991) MHC-restricted recognition of autologous melanoma by tumor-specific cytotoxic T cells. Evidence for restriction by a dominant HLA-A allele. J Immunol 146:1692PubMedGoogle Scholar
  11. 11.
    Pardoll D (2003) Does the immune system see tumors as foreign or self? Annu Rev Immunol 21:807PubMedCrossRefGoogle Scholar
  12. 12.
    Dunn GP, Old LJ, Schreiber RD (2004a) The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21:137CrossRefGoogle Scholar
  13. 13.
    Thomas L (1959) Discussion. In: Lawrence HS (ed) Cellular and humoral aspects of the hypersensitive states, Hoeber–Harper, New York, 529Google Scholar
  14. 14.
    Burnet FM (1964) Immunological factors in the process of carcinogenesis. Br Med Bull 20:154PubMedGoogle Scholar
  15. 15.
    Stutman O (1974) Tumor development after 3-methylcholanthrene in immunologically deficient athymic-nude mice. Science 183:534PubMedCrossRefGoogle Scholar
  16. 16.
    Stutman O (1979) Chemical carcinogenesis in nude mice: comparison between nude mice from homozygous and heterozygous matings and effect of age and carcinogen dose. J Natl Cancer Inst 2:353Google Scholar
  17. 17.
    Penn I (1988) Tumors of the immunocompromised patient. Annu Rev Med 39:63PubMedCrossRefGoogle Scholar
  18. 18.
    Kaplan DH, Shankaran V, Dighe AS, Stockert E, Aguet M, Old LJ, Schreiber RD (1998) Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice. Proc Natl Acad Sci USA 95:7556PubMedCrossRefGoogle Scholar
  19. 19.
    Street SE, Cretney E, Smyth MJ (2001) Perforin and interferon-gamma activities independently control tumor initiation, growth, and metastasis. Blood 97:192PubMedCrossRefGoogle Scholar
  20. 20.
    van den Broek ME, Kagi D, Ossendorp F, Toes R, Vamvakas S, Lutz WK, Melief CJ, Zinkernagel RM, Hengartner H (1996) Decreased tumor surveillance in perforin-deficient mice. J Exp Med 184:1781PubMedCrossRefGoogle Scholar
  21. 21.
    Smyth MJ, Thia KY, Street SE, Cretney E, Trapani JA, Taniguchi M, Kawano T, Pelikan SB, Crowe NY, Godfrey DI (2000a) Differential tumor surveillance by natural killer (NK) and NKT cells. Differential tumor surveillance by natural killer (NK) and NKT cells. J Exp Med 191:661CrossRefGoogle Scholar
  22. 22.
    Smyth MJ, Thia KY, Street SE, MacGregor D, Godfrey DI, Trapani JA (2000b) Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma. J Exp Med 192:755CrossRefGoogle Scholar
  23. 23.
    Shankaran V, Ikeda H, Bruce AT, White JM, Swanson PE, Old LJ, Schreiber RD (2001) IFNγ and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410:1107PubMedCrossRefGoogle Scholar
  24. 24.
    Smyth MJ, Crowe NY, Godfrey DI (2001) NK cells and NKT cells collaborate in host protection from methylcholanthrene-induced fibrosarcoma. Int Immunol 13:459PubMedCrossRefGoogle Scholar
  25. 25.
    Girardi M, Oppenheim DE, Steele CR, Lewis JM, Glusac E, Filler R, Hobby P, Sutton B, Tigelaar RE, Hayday AC (2001) Regulation of cutaneous malignancy by gammadelta T cells. Science 294:605PubMedCrossRefGoogle Scholar
  26. 26.
    Smyth MJ, Swann J, Cretney E, Zerafa N, Yokoyama WM, Hayakawa Y (2005) NKG2D function protects the host from tumor initiation. J Exp Med 202:583PubMedCrossRefGoogle Scholar
  27. 27.
    Dunn GP, Old LJ, Schreiber RD (2004b) The three Es of cancer immunoediting. Annu Rev Immunol 22:329CrossRefGoogle Scholar
  28. 28.
    Qin Z, Blankenstein T (2004) A cancer immunosurveillance controversy. Nat Immunol 5:3PubMedCrossRefGoogle Scholar
  29. 29.
    Blankenstein T, Qin Z (2003) Chemical carcinogens as foreign bodies and some pitfalls regarding cancer immune surveillance. Adv Cancer Res 90:179Google Scholar
  30. 30.
    Enzler T, Gillessen S, Manis JP, Ferguson D, Fleming J, Alt FW, Mihm M, Dranoff G (2003) Deficiencies of GM-CSF and interferon gamma link inflammation and cancer. J Exp Med 197:1213PubMedCrossRefGoogle Scholar
  31. 31.
    Blankenstein T (2005) The role of tumor stroma in the interaction between tumor and immune system. Curr Opin Immunol 17:180PubMedCrossRefGoogle Scholar
  32. 32.
    Chang CC, Campoli M, Ferrone S (2005a) Classical and nonclassical HLA class I antigen and NK Cell-activating ligand changes in malignant cells: current challenges and future directions. Adv Cancer Res 93:189CrossRefGoogle Scholar
  33. 33.
    Ericsson C, Seregard S, Bartolazzi A, Levitskaya E, Ferrone S, Kiessling R, Larsson O (2001) Association of HLA class I and class II antigen expression and mortality in uveal melanoma. Invest Ophthalmol Vis Sci 42:2153PubMedGoogle Scholar
  34. 34.
    Madjd Z, Spendlove I, Pinder SE, Ellis IO, Durrant LG (2005) Total loss of MHC class I is an independent indicator of good prognosis in breast cancer. Int J Cancer 117:248PubMedCrossRefGoogle Scholar
  35. 35.
    Ramnath N, Tan D, Li Q, Hylander BL, Bogner P, Ryes L, Ferrone S (2005) Is down-regulation of MHC class I antigen expression in human non-small cell lung cancer associated with prolonged survival? Cancer Immunol Immunother. (Epub) Sep 27:1 DOI: 10.1007/s00262-005-0085-7Google Scholar
  36. 36.
    Wang Z, Seliger B, Mike N, Momburg F, Knuth A, Ferrone S (1998) Molecular analysis of the HLA-A2 antigen loss by melanoma cells SK-MEL-29.1.22 and SK-MEL-29.1.29. Cancer Res 58:2149PubMedGoogle Scholar
  37. 37.
    Johnsen AK, Templeton DJ, Sy M, Harding CV (1999) Deficiency of transporter for antigen presentation (TAP) in tumor cells allows evasion of immune surveillance and increases tumorigenesis. J Immunol 163:4224PubMedGoogle Scholar
  38. 38.
    Lozupone F, Rivoltini L, Luciani F, Venditti M, Lugini L, Cova A, Squarcina P, Parmiani G, Belardelli F, Fais S (2003) Adoptive transfer of an anti-MART-127–35-specific CD8+ T cell clone leads to immunoselection of human melanoma antigen-loss variants in SCID mice. Eur J Immunol 33:556PubMedCrossRefGoogle Scholar
  39. 39.
    Jager E, Ringhoffer M, Altmannsberger M, Arand M, Karbach J, Jager D, Oesch F, Knuth A (1997) Immunoselection in vivo: independent loss of MHC class I and melanocyte differentiation antigen expression in metastatic melanoma. Int J Cancer 71:142PubMedCrossRefGoogle Scholar
  40. 40.
    Khong HT, Wang QJ, Rosenberg SA (2004) Identification of multiple antigens recognized by tumor-infiltrating lymphocytes from a single patient: tumor escape by antigen loss and loss of MHC expression. J Immunother 27:184PubMedCrossRefGoogle Scholar
  41. 41.
    Restifo NP, Marincola FM, Kawakami Y, Taubenberger J, Yannelli JR, Rosenberg SA (1996) Loss of functional β2-microglobulin in metastatic melanomas from five patients receiving immunotherapy. J Natl Cancer Inst 88:100PubMedGoogle Scholar
  42. 42.
    Chang CC, Campoli M, Restifo NP, Wang X, Ferrone S (2005b) Immune selection of hot-spot β2-microglobulin gene mutations, HLA-A2 allospecificity loss, and antigen-processing machinery component down-regulation in melanoma cells derived from recurrent metastases following immunotherapy. J Immunol 174:1462Google Scholar
  43. 43.
    Kloor M, Becker C, Benner A, Woerner SM, Gebert J, Ferrone S, von Knebel Doeberitz M (2005) Immunoselective pressure and human leukocyte antigen class I antigen machinery defects in microsatellite unstable colorectal cancers. Cancer Res 65:6418PubMedCrossRefGoogle Scholar
  44. 44.
    Ripberger E, Linnebacher M, Schwitalle Y, Gebert J, von Knebel Doeberitz M (2003) Identification of an HLA-A0201-restricted CTL epitope generated by a tumor-specific frameshift mutation in a coding microsatellite of the OGT gene. J Clin Immunol 23:415PubMedCrossRefGoogle Scholar
  45. 45.
    Darwin C (1859) Natural selection. In: Burrow JW (ed) The origin of species by means of natural selection: the preservation of favored races in the struggle for life, Penguin Books Ltd, London, pp 162Google Scholar
  46. 46.
    Hahn WC, Weinberg RA (2002) Rules for making human tumor cells. N Engl J Med 347:1593PubMedCrossRefGoogle Scholar
  47. 47.
    Lehmann F, Marchand M, Hainaut P, Pouillart P, Sastre X, Ikeda H, Boon T, Coulie PG (1995) Differences in the antigens recognized by cytolytic T cells on two successive metastases of a melanoma patient are consistent with immune selection. Eur J Immunol 25:340PubMedGoogle Scholar
  48. 48.
    Yamshchikov GV, Mullins DW, Chang CC, Ogino T, Thompson L, Presley J, Galavotti H, Aquila W, Deacon D, Ross W, Patterson JW, Engelhard VH, Ferrone S, Slingluff CL Jr (2005) Sequential immune escape and shifting of T cell responses in a long-term survivor of melanoma. J Immunol 174:6863PubMedGoogle Scholar
  49. 49.
    Seliger B, Ritz U, Abele R, Bock M, Tampe R, Sutter G, Drexler I, Huber C, Ferrone S (2001) Immune escape of melanoma: first evidence of structural alterations in two distinct components of the MHC class I antigen processing pathway. Cancer Res 61:8647PubMedGoogle Scholar
  50. 50.
    Parmiani G, Castelli C, Dalerba P, Mortarini R, Rivoltini L, Marincola FM, Anichini A (2002) Cancer immunotherapy with peptide-based vaccines: what have we achieved? Where are we going? J Natl Cancer Inst 94:805PubMedGoogle Scholar
  51. 51.
    Dezfouli S, Hatzinisiriou I, Ralph SJ (2005) Use of cytokines in cancer vaccines/immunotherapy: recent developments improve survival rates for patients with metastatic malignancy. Curr Pharm Des 11:3511PubMedCrossRefGoogle Scholar
  52. 52.
    Adams GP, Weiner LM (2005) Monoclonal antibody therapy of cancer. Nat Biotechnol 23:1147PubMedCrossRefGoogle Scholar
  53. 53.
    Coiffier B (2004) Effective immunochemotherapy for aggressive non-Hodgkin’s lymphoma. Semin Oncol 31(1 Suppl 2): 7PubMedCrossRefGoogle Scholar
  54. 54.
    Finn RS, Slamon DJ (2003) Monoclonal antibody therapy for breast cancer: herceptin. Cancer Chemother Biol Response Modif 21:223PubMedGoogle Scholar
  55. 55.
    Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N (2005) Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673Google Scholar
  56. 56.
    O’Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J (1997) Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88:277PubMedCrossRefGoogle Scholar
  57. 57.
    Kerbel R, Folkman J (2002) Clinical translation of angiogenesis inhibitors. Nat Rev Cancer 2:727PubMedCrossRefGoogle Scholar
  58. 58.
    Folkman J (2006) Angiogenesis. Annu Rev Med 57:1PubMedCrossRefGoogle Scholar
  59. 59.
    Spiotto MT, Rowley DA, Schreiber H (2004) Bystander elimination of antigen loss variants in established tumors. Nat Med 10:294PubMedCrossRefGoogle Scholar
  60. 60.
    Quaglino E, Rolla S, Iezzi M, Spadaro M, Musiani P, De Giovanni C, Lollini PL, Lanzardo S, Forni G, Sanges R, Crispi S, De Luca P, Calogero R, Cavallo F (2004) Concordant morphologic and gene expression data show that a vaccine halts HER-2/neu preneoplastic lesions. J Clin Invest 113:709PubMedCrossRefGoogle Scholar
  61. 61.
    Lollini PL, Cavallo F, Nanni P, Forni G (2006) Vaccines for tumour prevention. Nat Rev Cancer 6:204PubMedCrossRefGoogle Scholar
  62. 62.
    Peltenburg LT, Schrier PI (1994) Transcriptional suppression of HLA-B expression by c-Myc is mediated through the core promoter elements. Immunogenetics 40:54PubMedCrossRefGoogle Scholar
  63. 63.
    Staege MS, Lee SP, Frisan T, Mautner J, Scholz S, Pajic A, Rickinson AB, Masucci MG, Polack A, Bornkamm GW (2002) MYC overexpression imposes a nonimmunogenic phenotype on Epstein-Barr virus-infected B cells. Proc Natl Acad Sci USA 99:4550PubMedCrossRefGoogle Scholar
  64. 64.
    Atkins D, Breuckmann A, Schmahl GE, Binner P, Ferrone S, Krummenauer F, Storkel S, Seliger B (2004) MHC class I antigen processing pathway defects, ras mutations and disease stage in colorectal carcinoma. Int J Cancer 109:265PubMedCrossRefGoogle Scholar
  65. 65.
    Herrmann F, Lehr HA, Drexler I, Sutter G, Hengstler J, Wollscheid U, Seliger B (2004) HER-2/neu-mediated regulation of components of the MHC class I antigen-processing pathway. Cancer Res 64:215PubMedCrossRefGoogle Scholar
  66. 66.
    Karre K (2002) NK cells, MHC class I molecules and the missing self. Scand J Immunol 55:221PubMedCrossRefGoogle Scholar
  67. 67.
    Vetter CS, Groh V, thor Straten P, Spies T, Brocker EB, Becker JC (2002) Expression of stress-induced MHC class I related chain molecules on human melanoma. J Invest Dermatol 118:600PubMedCrossRefGoogle Scholar
  68. 68.
    Pende D, Rivera P, Marcenaro S, Chang CC, Biassoni R, Conte R, Kubin M, Cosman D, Ferrone S, Moretta L, Moretta A (2002) Major histocompatibility complex class I-related chain A and UL16-binding protein expression on tumor cell lines of different histotypes: analysis of tumor susceptibility to NKG2D-dependent natural killer cell cytotoxicity. Cancer Res 62:6178PubMedGoogle Scholar
  69. 69.
    Cerwenka A, Baron JL, Lanier LL (2001) Ectopic expression of retinoic acid early inducible-1 gene (RAE-1) permits natural killer cell-mediated rejection of a MHC class I-bearing tumor in vivo. Proc Natl Acad Sci USA 98:11521PubMedCrossRefGoogle Scholar
  70. 70.
    Groh V, Wu J, Yee C, Spies T (2002) Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature 419:734PubMedCrossRefGoogle Scholar
  71. 71.
    Wu JD, Higgins LM, Steinle A, Cosman D, Haugk K, Plymate SR (2004) Prevalent expression of the immunostimulatory MHC class I chain-related molecule is counteracted by shedding in prostate cancer. J Clin Invest 114:560PubMedCrossRefGoogle Scholar
  72. 72.
    Willimsky G, Blankenstein T (2005) Sporadic immunogenic tumours avoid destruction by inducing T-cell tolerance. Nature 437:141PubMedCrossRefGoogle Scholar
  73. 73.
    Chang CC, Campoli M, Ferrone S (2004) HLA class I antigen expression in malignant cells: why does it not always correlate with CTL-mediated lysis? Curr Opin Immunol 16:644PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  1. 1.Department of Structural BiologyHauptman-Woodward InstituteBuffaloUSA
  2. 2.Department of ImmunologyRoswell Park Cancer InstituteBuffaloUSA

Personalised recommendations