Cancer Immunology, Immunotherapy

, Volume 57, Issue 11, pp 1719–1726 | Cite as

Molecular mechanisms of MHC class I abnormalities and APM components in human tumors

  • Barbara SeligerEmail author
Symposium Paper


Tumor immune escape plays a critical role in cancer, but the mechanisms involved in this process have still to be defined. In the recent years, progress has been made in understanding how peptides presented by MHC class I molecules were generated, in particular which proteases are involved in this process and how intracellular pathways influence antigen presentation in professional antigen-presenting cells and in various types of malignancies. Different MHC class I abnormalities have been found in solid tumors of distinct origin, but also in hematopoietic diseases. These include structural alterations such as total, haplotype and allelic loss of the MHC class I heavy chain, deletions and point mutations, in particular in β2-microglobulin and TAP1 as well as dysregulation of various components of the MHC class I antigen processing machinery (APM), which could occur at the epigenetic, transcriptional and posttranscriptional level. The lack or downmodulation of the expression of single or multiple components of the MHC class I antigen processing pathway may avoid the recognition of tumor cells by tumor-specific CD8+ cytotoxic T lymphocytes. This review will give an overview of the underlying molecular mechanisms of MHC class I abnormalities in human tumors of distinct histology, which also might have an impact on the design of T cell-based immunotherapies.


Antigen processing Gene regulation Immune escape MHC class I Tumors 



Amino acid


Antigen-presenting cell


Antigen processing machinery


Aminopeptidase N


Bleomycin hydrolase




Loss of heterozygosity


Colony-stimulating factor


Cytotoxic T lymphocytes




Dendritic cells


Endoplasmic reticulum


ER aminopeptidase associated with antigen processing


Granulocyte-macrophage colony stimulating factor


Heavy chain


Head and neck squamous cell carcinoma






Leucin aminopeptidase


Low molecular weight proteins


Loss of heterozygosity




Major histocompatibility complex


Natural killer


Proteasome activator


Protein disulfide isomerase


Peptide loading complex


Renal cell carcinoma


Transporter associated with antigen processing


Transforming growth factor




Tripeptidyl peptidase II


Trichostatin A


Valproic acid



This work was sponsored by the DFG projects (SE581/9-1, SE581/9-2, SE581/11-1). We would like to thank Anne Wasilewski for excellent secretarial help.


  1. 1.
    Alpan RS, Zhang M, Pardee AB (1996) Cell cycle-dependent expression of TAP1, TAP2, and HLA-B27 messenger RNAs in a human breast cancer cell line. Cancer Res 56:4358–4361PubMedGoogle Scholar
  2. 2.
    Aptsiauri N, Cabrera T, Mendez R, Garcia-Lora A, Ruiz-Cabello F, Garrido F (2007) Role of altered expression of HLA class I molecules in cancer progression. Adv Exp Med Biol 601:123–131PubMedGoogle Scholar
  3. 3.
    Atkins D, Ferrone S, Schmahl GE, Storkel S, Seliger B (2004) Down-regulation of HLA class I antigen processing molecules: an immune escape mechanism of renal cell carcinoma? J Urol 171:885–889PubMedCrossRefGoogle Scholar
  4. 4.
    Bui JD, Carayannopoulos LN, Lanier LL, Yokoyama WM, Schreiber RD (2006) IFN-dependent down-regulation of the NKG2D ligand H60 on tumors. J Immunol 176:905–913PubMedGoogle Scholar
  5. 5.
    Cabrera CM (2007) The double role of the endoplasmic reticulum chaperone tapasin in peptide optimization of HLA class I molecules. Scand J Immunol 65:487–493PubMedCrossRefGoogle Scholar
  6. 6.
    Cabrera T, Maleno I, Collado A, Lopez Nevot MA, Tait BD, Garrido F (2007) Analysis of HLA class I alterations in tumors: choosing a strategy based on known patterns of underlying mechanisms. Tissue Antigens 69(Suppl 1):264–268PubMedCrossRefGoogle Scholar
  7. 7.
    Chambers JE, Jessop CE, Bulleid NJ (2007) Formation of a MHC Class I-tapasin mixed disulfide indicates a change in spatial organization of the peptide loading complex during assembly. J Biol Chem 283(4):1862–1869PubMedCrossRefGoogle Scholar
  8. 8.
    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 281:18763–18773PubMedCrossRefGoogle Scholar
  9. 9.
    Chang SC, Momburg F, Bhutani N, Goldberg AL (2005) The ER aminopeptidase, ERAP1, trims precursors to lengths of MHC class I peptides by a “molecular ruler” mechanism. Proc Natl Acad Sci USA 102:17107–17112PubMedCrossRefGoogle Scholar
  10. 10.
    Chang CC, Ferrone S (2007) Immune selective pressure and HLA class I antigen defects in malignant lesions. Cancer Immunol Immunother 56:227–236PubMedCrossRefGoogle Scholar
  11. 11.
    Chen HL, Gabrilovich D, Tampe R, Girgis KR, Nadaf S, Carbone DP (1996) A functionally defective allele of TAP1 results in loss of MHC class I antigen presentation in a human lung cancer. Nat Genet 13:210–213PubMedCrossRefGoogle Scholar
  12. 12.
    Deng XL, Chen W, Cai MY, Wei DP (2003) Expression of class I MHC molecule, HSP70 and TAP in human hepatocellular carcinoma. World J Gastroenterol 9:1853–1855PubMedGoogle Scholar
  13. 13.
    Dunn GP, Old LJ, Schreiber RD (2004) The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21:137–148PubMedCrossRefGoogle Scholar
  14. 14.
    Dunn GP, Koebel CM, Schreiber RD (2006) Interferons, immunity and cancer immunoediting. Nat Rev Immunol 6:836–848PubMedCrossRefGoogle Scholar
  15. 15.
    Fernández MA, Ruiz-Cabello F, Oliva MR, Cabrera T, Jimenez P, López Nevot MA, Garrido F (2000) Beta2-microglobulin gene mutation is not a common mechanism of HLA class I total loss in human tumors. Int J Clin Lab Res 30:87–92PubMedGoogle Scholar
  16. 16.
    Fruci D, Ferracuti S, Limongi MZ, Cunsolo V, Giorda E, Fraioli R, Sibilio L, Carroll O, Hattori A, van Endert PM et al (2006) Expression of endoplasmic reticulum aminopeptidases in EBV-B cell lines from healthy donors and in leukemia/lymphoma, carcinoma, and melanoma cell lines. J Immunol 176:4869–4879PubMedGoogle Scholar
  17. 17.
    Goldberg AL, Cascio P, Saric T, Rock KL (2002) The importance of the proteasome and subsequent proteolytic steps in the generation of antigenic peptides. Mol Immunol 39:147–164PubMedCrossRefGoogle Scholar
  18. 18.
    Gubler B, Daniel S, Armandola EA, Hammer J, Caillat-Zucman S, van Endert PM (1998) Substrate selection by transporters associated with antigen processing occurs during peptide binding to TAP. Mol Immunol 35:427–433PubMedCrossRefGoogle Scholar
  19. 19.
    Guo Y, Yang T, Liu X, Lu S, Wen J, Durbin JE, Liu Y, Zheng P (2002) Cis elements for transporter associated with antigen-processing-2 transcription: two new promoters and an essential role of the IFN response factor binding element in IFN-gamma-mediated activation of the transcription initiator. Int Immunol 14:189–200PubMedCrossRefGoogle Scholar
  20. 20.
    Hallermalm K, Seki K, Wei C, Castelli C, Rivoltini L, Kiessling R, Levitskaya J (2001) Tumor necrosis factor-alpha induces coordinated changes in major histocompatibility class I presentation pathway, resulting in increased stability of class I complexes at the cell surface. Blood 98:1108–1115PubMedCrossRefGoogle Scholar
  21. 21.
    Hammer GE, Gonzalez F, Champsaur M, Cado D, Shastri N (2006) The aminopeptidase ERAAP shapes the peptide repertoire displayed by major histocompatibility complex class I molecules. Nat Immunol 7:103–112PubMedCrossRefGoogle Scholar
  22. 22.
    Hammer GE, Gonzalez F, James E, Nolla H, Shastri N (2007) In the absence of aminopeptidase ERAAP, MHC class I molecules present many unstable and highly immunogenic peptides. Nat Immunol 8:101–108PubMedCrossRefGoogle Scholar
  23. 23.
    Hammer GE, Kanaseki T, Shastri N (2007) The final touches make perfect the peptide-MHC class I repertoire. Immunity 26:397–406PubMedCrossRefGoogle Scholar
  24. 24.
    Hicklin DJ, Kageshita T, Ferrone S (1996) Development and characterization of rabbit antisera to human MHC-linked transporters associated with antigen processing. Tissue Antigens 48:38–46PubMedCrossRefGoogle Scholar
  25. 25.
    Hirata T, Yamamoto H, Taniguchi H, Horiuchi S, Oki M, Adachi Y, Imai K, Shinomura Y (2007) Characterization of the immune escape phenotype of human gastric cancers with and without high-frequency microsatellite instability. J Pathol 211:516–523PubMedCrossRefGoogle Scholar
  26. 26.
    Jensen PE (2007) Recent advances in antigen processing and presentation. Nat Immunol 8:1041–1048PubMedCrossRefGoogle Scholar
  27. 27.
    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 83:91–97PubMedCrossRefGoogle Scholar
  28. 28.
    Kawamura J, Shimada Y, Kitaichi H, Komoto I, Hashimoto Y, Kaganoi J, Miyake M, Yamasaki S, Kondo K, Imamura M (2007) Clinicopathological significance of aminopeptidase N/CD13 expression in human gastric carcinoma. Hepatogastroenterology 54:36–40PubMedGoogle Scholar
  29. 29.
    Kehlen A, Gohring B, Langner J, Riemann D (1998) Regulation of the expression of aminopeptidase A, aminopeptidase N/CD13 and dipeptidylpeptidase IV/CD26 in renal carcinoma cells and renal tubular epithelial cells by cytokines and cAMP-increasing mediators. Clin Exp Immunol 111:435–441PubMedCrossRefGoogle Scholar
  30. 30.
    Kehlen A, Lendeckel U, Dralle H, Langner J, Hoang-Vu C (2003) Biological significance of aminopeptidase N/CD13 in thyroid carcinomas. Cancer Res 63:8500–8506PubMedGoogle Scholar
  31. 31.
    Khan AN, Gregorie CJ, Tomasi TB (2007) Histone deacetylase inhibitors induce TAP, LMP, Tapasin genes and MHC class I antigen presentation by melanoma cells. Cancer Immunol Immunother 57(5):647–654PubMedCrossRefGoogle Scholar
  32. 32.
    Kienast A, Preuss M, Winkler M, Dick TP (2007) Redox regulation of peptide receptivity of major histocompatibility complex class I molecules by ERp57 and tapasin. Nat Immunol 8:864–872PubMedCrossRefGoogle Scholar
  33. 33.
    Koebel CM, Vermi W, Swann JB, Zerafa N, Rodig SJ, Old LJ, Smyth MJ, Schreiber RD (2007) Adaptive immunity maintains occult cancer in an equilibrium state. Nature 450:903–907PubMedCrossRefGoogle Scholar
  34. 34.
    Li J, Schuler-Thurner B, Schuler G, Huber C, Seliger B (2001) Bipartite regulation of different components of the MHC class I antigen-processing machinery during dendritic cell maturation. Int Immunol 13:1515–1523PubMedCrossRefGoogle Scholar
  35. 35.
    Madden DR (1995) The three-dimensional structure of peptide-MHC complexes. Annu Rev Immunol 13:587–622PubMedCrossRefGoogle Scholar
  36. 36.
    Maleno I, Lopez Nevot MA, Seliger B, Garrido F (2004) Low frequency of HLA haplotype loss associated with loss of heterozygocity in chromosome region 6p21 in clear renal cell carcinomas. Int J Cancer 109:636–638PubMedCrossRefGoogle Scholar
  37. 37.
    Manning J, Indrova M, Lubyova B, Pribylova H, Bieblova J, Hejnar J, Simova J, Jandlova T, Bubenik J, Reinis M (2008) Induction of MHC class I molecule cell surface expression and epigenetic activation of antigen-processing machinery components in a murine model for human papilloma virus 16-associated tumours. Immunology 123:218–227PubMedGoogle Scholar
  38. 38.
    Mehta AM, Jordanova ES, Kenter GG, Ferrone S, Fleuren GJ (2008) Association of antigen processing machinery and HLA class I defects with clinicopathological outcome in cervical carcinoma. Cancer Immunol Immunother 57:197–206PubMedCrossRefGoogle Scholar
  39. 39.
    Meissner M, Reichert TE, Kunkel M, Gooding W, Whiteside TL, Ferrone S, Seliger B (2005) Defects in the human leukocyte antigen class I antigen processing machinery in head and neck squamous cell carcinoma: association with clinical outcome. Clin Cancer Res 11:2552–2560PubMedCrossRefGoogle Scholar
  40. 40.
    Mendez R, Rodriguez T, Del Campo A, Monge E, Maleno I, Aptsiauri N, Jimenez P, Pedrinaci S, Pawelec G, Ruiz-Cabello F, Garrido F (2008) Characterization of HLA class I altered phenotypes in a panel of human melanoma cell lines. Cancer Immunol Immunother 57(5):719–729PubMedCrossRefGoogle Scholar
  41. 41.
    Menrad A, Speicher D, Wacker J, Herlyn M (1993) Biochemical and functional characterization of aminopeptidase N expressed by human melanoma cells. Cancer Res 53:1450–1455PubMedGoogle Scholar
  42. 42.
    Nie Y, Yang G, Song Y, Zhao X, So C, Liao J, Wang LD, Yang CS (2001) DNA hypermethylation is a mechanism for loss of expression of the HLA class I genes in human esophageal squamous cell carcinomas. Carcinogen 22:1615–1623CrossRefGoogle Scholar
  43. 43.
    Paschen A, Méndez RM, Jimenez P, Sucker A, Ruiz-Cabello F, Song M, Garrido F, Schadendorf D (2003) Complete loss of HLA class I antigen expression on melanoma cells: a result of successive mutational events. Int J Cancer 103:759–767PubMedCrossRefGoogle Scholar
  44. 44.
    Petersson M, Charo J, Salazar-Onfray F, Noffz G, Mohaupt M, Qin Z, Klein G, Blankenstein T, Kiessling R (1998) Constitutive IL-10 production accounts for the high NK sensitivity, low MHC class I expression, and poor transporter associated with antigen processing (TAP)-1/2 function in the prototype NK target YAC-1. J Immunol 161:2099–2105PubMedGoogle Scholar
  45. 45.
    Ramal LM, Maleno I, Cabrera T, Collado A, Ferron A, Lopez-Nevot MA, Garrido F (2000) Molecular strategies to define HLA haplotype loss in microdissected tumor cells. Hum Immunol 61:1001–12PubMedCrossRefGoogle Scholar
  46. 46.
    Rammensee HG, Friede T, Stevanoviic S (1995) MHC ligands and peptide motifs: first listing. Immunogenetics 41:178–228PubMedCrossRefGoogle Scholar
  47. 47.
    Ramnath N, Tan D, Li Q, Hylander BL, Bogner P, Ryes L, Ferrone S (2006) Is downregulation of MHC class I antigen expression in human non-small cell lung cancer associated with prolonged survival? Cancer Immunol Immunother 55:891–899PubMedCrossRefGoogle Scholar
  48. 48.
    Reits EA, Hodge JW, Herberts CA, Groothuis TA, Chakraborty M, Wansley EK, Camphausen K, Luiten RM, de Ru AH, Neijssen J, Griekspoor A, Mesman E, Verreck FA, Spits H, Schlom J, van Veelen P, Neefjes JJ (2006) Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J Exp Med 203:1259–1271PubMedCrossRefGoogle Scholar
  49. 49.
    Ritz U, Momburg F, Pilch H, Huber C, Maeurer MJ, Seliger B (2001) Deficient expression of components of the MHC class I antigen processing machinery in human cervical carcinoma. Int J Oncol 19:1211–1220PubMedGoogle Scholar
  50. 50.
    Rodriguez T, Mendez R, Del Campo A, Jimenez P, Aptsiauri N, Garrido F, Ruiz-Cabello F (2007) Distinct mechanisms of loss of IFN-gamma mediated HLA class I inducibility in two melanoma cell lines. BMC Cancer 7:34PubMedCrossRefGoogle Scholar
  51. 51.
    Romero JM, Jiménez P, Cabrera T, Cózar 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 113:605–610PubMedCrossRefGoogle Scholar
  52. 52.
    Santos SG, Campbell EC, Lynch S, Wong V, Antoniou AN, Powis SJ (2007) Major histocompatibility complex class I-ERp57-tapasin interactions within the peptide-loading complex. J Biol Chem 282:17587–17593PubMedCrossRefGoogle Scholar
  53. 53.
    Saveanu L, Carroll O, Lindo V, Del Val M, Lopez D, Lepelletier Y, Greer F, Schomburg L, Fruci D, Niedermann G, van Endert PM (2005) Concerted peptide trimming by human ERAP1 and ERAP2 aminopeptidase complexes in the endoplasmic reticulum. Nat Immunol 6:689–697PubMedCrossRefGoogle Scholar
  54. 54.
    Seliger B, Hohne A, Knuth A, Bernhard H, Ehring B, Tampe R, Huber C (1996) Reduced membrane major histocompatibility complex class I density and stability in a subset of human renal cell carcinomas with low TAP and LMP expression. Clin Cancer Res 2:1427–1433PubMedGoogle Scholar
  55. 55.
    Seliger B, Hohne A, Knuth A, Bernhard H, Meyer T, Tampe R, Momburg F, Huber C (1996) Analysis of the major histocompatibility complex class I antigen presentation machinery in normal and malignant renal cells: evidence for deficiencies associated with transformation and progression. Cancer Res 56:1756–1760PubMedGoogle Scholar
  56. 56.
    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 61:8647–8650PubMedGoogle Scholar
  57. 57.
    Seliger B (2005) Strategies of tumor immune evasion. BioDrugs 19:347–354PubMedCrossRefGoogle Scholar
  58. 58.
    Seliger B, Ritz U, Ferrone S (2006) Molecular mechanisms of HLA class I antigen abnormalities following viral infection and transformation. Int J Cancer 118:129–138PubMedCrossRefGoogle Scholar
  59. 59.
    Sigalotti L, Fratta E, Coral S, Tanzarella S, Danielli R, Colizzi F, Fonsatti E, Traversari C, Altomonte M, Maio M (2004) Intratumor heterogeneity of cancer/testis antigens expression in human cutaneous melanoma is methylation-regulated and functionally reverted by 5-aza-2´-deoxycytidine. Cancer Res 64:9167–9171PubMedCrossRefGoogle Scholar
  60. 60.
    Spiotto MT, Yu P, Rowley DA, Nishimura MI, Meredith SC, Gajewski TF, Fu YX, Schreiber H (2002) Increasing tumor antigen expression overcomes “ignorance” to solid tumors via crosspresentation by bone marrow-derived stromal cells. Immunity 17:737–747PubMedCrossRefGoogle Scholar
  61. 61.
    van Endert PM, Saveanu L, Hewitt EW, Lehner P (2002) Powering the peptide pump: TAP crosstalk with energetic nucleotides. Trends Biochem Sci 27:454–461PubMedCrossRefGoogle Scholar
  62. 62.
    Varona A, Blanco L, Lopez JI, Gil J, Agirregoitia E, Irazusta J, Larrinaga G (2007) Altered levels of acid, basic, and neutral peptidase activity and expression in human clear cell renal cell carcinoma. Am J Physiol Renal Physiol 292:F780–F788PubMedCrossRefGoogle Scholar
  63. 63.
    Vertuani S, De Geer A, Levitsky V, Kogner P, Kiessling R, Levitskaya J (2003) Retinoids act as multistep modulators of the major histocompatibility class I presentation pathway and sensitize neuroblastomas to cytotoxic lymphocytes. Cancer Res 63:8006–8013PubMedGoogle Scholar
  64. 64.
    Vertuani S, Dubrovska E, Levitsky V, Jager MJ, Kiessling R, Levitskaya J (2007) Retinoic acid elicits cytostatic, cytotoxic and immunomodulatory effects on uveal melanoma cells. Cancer Immunol Immunother 56:193–204PubMedCrossRefGoogle Scholar
  65. 65.
    Vitale M, Pelusi G, Taroni B, Gobbi G, Micheloni C, Rezzani R, Donato F, Wang X, Ferrone S (2005) HLA class I antigen down-regulation in primary ovary carcinoma lesions: association with disease stage. Clin Cancer Res 11:67–72PubMedGoogle Scholar
  66. 66.
    Yewdell JW (2005) The seven dirty little secrets of major histocompatibility complex class I antigen processing. Immunol Rev 207:8–18PubMedCrossRefGoogle Scholar
  67. 67.
    Zeidler R, Eissner G, Meissner P, Uebel S, Tampe R, Lazis S, Hammerschmidt W (1997) Downregulation of TAP1 in B lymphocytes by cellular and Epstein-Barr virus-encoded interleukin–10. Blood 90:2390–2397PubMedGoogle Scholar
  68. 68.
    Zhu K, Wang J, Zhu J, Jiang J, Shou J, Chen X (1999) p53 induces TAP1 and enhances the transport of MHC class I peptides. Oncogene 18:7740–7747PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  1. 1.Martin-Luther-Universität Halle-Wittenberg, Institute of Medical ImmunologyHalle (Saale)Germany

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