MHC class I antigens, immune surveillance, and tumor immune escape

Oncogenic transformation in human and experimental animals is not necessarily followed by the appearance of a tumor mass. The immune system of the host can recognize tumor antigens by the presentation of small antigenic peptides to the receptor of cytotoxic T‐lymphocytes (CTLs) and reject the nascent tumor. However, cancer cells can sometimes escape these specific T‐cell immune responses in the course of somatic (genetic and phenotypic) clonal evolution. Among the tumor immune escape mechanisms described to date, the alterations in the expression of major histocompatibility complex (MHC) molecules play a crucial step in tumor development due to the role of MHC antigens in antigen presentation to T‐lymphocytes and the regulation of natural killer cell (NK) cell function. In this work, we have (1) updated information on the mechanisms that allow CTLs to recognize tumor antigens after antigen processing by transformed cells, (2) described the altered MHC class I phenotypes that are commonly found in human tumors, (3) summarized the molecular mechanisms responsible for MHC class I alteration in human tumors, (4) provided evidence that these altered human leukocyte antigens (HLA) class I phenotypes are detectable as result of a T‐cell immunoselection of HLA class I‐deficient variants by an immunecompetent host, and (5) presented data indicating the MHC class I phenotype and the immunogenicity of experimental metastatic tumors change drastically when tumors develop in immunodeficient mice. © 2003 Wiley‐Liss, Inc.

[1]  X. Sastre,et al.  Differences in the antigens recognized by cytolytic T cells on two successive metastases of a melanoma patient are consistent with immune selection , 1995, European journal of immunology.

[2]  P. Stern,et al.  Natural history of HLA expression during tumour development. , 1993, Immunology today.

[3]  J. Yewdell,et al.  Identification of human cancers deficient in antigen processing , 1993, The Journal of experimental medicine.

[4]  R. Schreiber,et al.  Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[5]  P. Bruggen,et al.  Tumor antigens recognized by T lymphocytes. , 1994, Annual review of immunology.

[6]  P Parham,et al.  Structure, function, and diversity of class I major histocompatibility complex molecules. , 1990, Annual review of biochemistry.

[7]  D. Templeton,et al.  Deficiency of transporter for antigen presentation (TAP) in tumor cells allows evasion of immune surveillance and increases tumorigenesis. , 1999, Journal of immunology.

[8]  M. Llano,et al.  NK cell recognition of non-classical HLA class I molecules. , 2000, Seminars in immunology.

[9]  D. Carbone,et al.  Structural and functional analysis of β2 microglobulin abnormalities in human lung and breast cancer , 1996 .

[10]  F. Garrido,et al.  H–2-like specificities of foreign haplotypes appearing on a mouse sarcoma after vaccinia virus infection , 1976, Nature.

[11]  F. Garrido,et al.  MHC class I‐deficient metastatic tumor variants immunoselected by T lymphocytes originate from the coordinated downregulation of APM components , 2003, International journal of cancer.

[12]  F. Garrido,et al.  Characterization of a gastric tumor cell line defective in MHC class I inducibility by both α- and γ-interferon , 1996 .

[13]  C. Meijer,et al.  Loss of transporter protein, encoded by the TAP-1 gene, is highly correlated with loss of HLA expression in cervical carcinomas , 1994, The Journal of experimental medicine.

[14]  F. Momburg,et al.  Generation, intracellular transport and loading of peptides associated with MHC class I molecules. , 1997, Current opinion in immunology.

[15]  M. Mareel,et al.  The invasive phenotypes , 1990, Cancer and Metastasis Reviews.

[16]  F. Garrido,et al.  Molecular strategies to define HLA haplotype loss in microdissected tumor cells. , 2000, Human immunology.

[17]  F. Garrido,et al.  Influence of class I H-2 gene expression on local tumor growth. Description of a model obtained from clones derived from a solid BALB/c tumor. , 1986, Experimental and clinical immunogenetics.

[18]  H. Zinszner,et al.  DNA binding of regulatory factors interacting with MHC‐class‐I gene enhancer correlates with MHC‐class‐I transcriptional level in class‐I‐defective cell lines , 1991, International journal of cancer. Supplement = Journal international du cancer. Supplement.

[19]  B. Seliger,et al.  HLA class I antigen abnormalities and immune escape by malignant cells. , 2002, Seminars in cancer biology.

[20]  R. Schreiber,et al.  IFNγ and lymphocytes prevent primary tumour development and shape tumour immunogenicity , 2001, Nature.

[21]  F. Garrido,et al.  Multiple mechanisms generate HLA class I altered phenotypes in laryngeal carcinomas: high frequency of HLA haplotype loss associated with loss of heterozygosity in chromosome region 6p21 , 2002, Cancer Immunology, Immunotherapy.

[22]  F. Garrido,et al.  Rexpression of HLA class I antigens and restoration of antigen‐specific CTL response in melanoma cells following 5‐aza‐2′‐deoxycytidine treatment , 2001, International journal of cancer.

[23]  J. Trowsdale,et al.  Genetic and functional relationships between MHC and NK receptor genes. , 2001, Immunity.

[24]  P. Le Bouteiller.  HLA class I chromosomal region, genes, and products: facts and questions. , 1994, Critical reviews in immunology.

[25]  G. Klein,et al.  Demonstration of resistance against methylcholanthrene-induced sarcomas in the primary autochthonous host. , 1960, Cancer research.

[26]  M. R. Oliva,et al.  MHC CLASS I AND II ANTIGENS ON GASTRIC CARCINOMAS AND AUTOLOGOUS MUCOSA , 1989, Journal of immunogenetics.

[27]  F. Brasseur,et al.  Mutations of the beta2-microglobulin gene result in a lack of HLA class I molecules on melanoma cells of two patients immunized with MAGE peptides. , 1998, Tissue antigens.

[28]  J. Zeuthen,et al.  In vivo and in vitro generation of a new altered HLA phenotype in melanoma‐tumour‐cell variants expressing a single HLA‐class‐I allele , 1998, International journal of cancer.

[29]  J. G. van den Tweel,et al.  HLA class I expression and chromosomal deletions at 6p and 15q in head and neck squamous cell carcinomas. , 1999, Tissue antigens.

[30]  J. Blay,et al.  The host-tumor immune conflict: from immunosuppression to resistance and destruction. , 1997, Immunology today.

[31]  M. R. Oliva,et al.  A new beta 2 microglobulin mutation found in a melanoma tumor cell line. , 1999, Tissue antigens.

[32]  E. Mbidde,et al.  Relevance of AIDS treatment with two nucleoside analogues alone , 1999, The Lancet.

[33]  K. Hui,et al.  Locus-specific transcriptional control of HLA genes. , 1992, Journal of immunology.

[34]  P. Stern,et al.  Implications for immunosurveillance of altered HLA class I phenotypes in human tumours. , 1997, Immunology today.

[35]  L. Kaer,et al.  Tapasin: an ER chaperone that controls MHC class I assembly with peptide. , 2001, Trends in immunology.

[36]  J. Tschopp,et al.  Melanoma Cell Expression of Fas(Apo-1/CD95) Ligand: Implications for Tumor Immune Escape , 1996, Science.

[37]  U. Ritz,et al.  Deficient expression of components of the MHC class I antigen processing machinery in human cervical carcinoma. , 2001, International journal of oncology.

[38]  K. Wright,et al.  Loss of Interferon-γ Inducibility of TAP1 and LMP2 in a Renal Cell Carcinoma Cell Line , 2000 .

[39]  F. Garrido,et al.  Further evidence for derepression of H–2 and Ia-like specificities of foreign haplotypes in mouse tumour cell lines , 1976, Nature.

[40]  P. Cresswell,et al.  Mechanisms of MHC class I--restricted antigen processing. , 1998, Annual review of immunology.

[41]  L. T. Peltenburg,et al.  Transcriptional suppression of HLA-B expression by c-Myc is mediated through the core promoter elements , 2004, Immunogenetics.

[42]  I. Algarra,et al.  Heterogeneity of MHC‐class‐I antigens in clones of methylcholanthrene‐induced tumors. Implications for local growth and metastasis , 1991, International journal of cancer. Supplement = Journal international du cancer. Supplement.

[43]  R. Tampé,et al.  Function of the transport complex TAP in cellular immune recognition. , 1999, Biochimica et biophysica acta.

[44]  A. Aránega,et al.  HLA class I and II expression in rhabdomyosarcomas. , 1991, Immunobiology.

[45]  P. Murphy.  Electrophoretic evidence that selection reduces ecological overlap in marine limpets , 1976, Nature.

[46]  F. Garrido,et al.  High frequency of altered HLA class I phenotypes in invasive colorectal carcinomas. , 1996, Tissue antigens.

[47]  F. Burnet.  The concept of immunological surveillance. , 1970, Progress in experimental tumor research.

[48]  G. Klein,et al.  A weakly tumorigenic phenotype with high mhc class‐i expression is associated with high metastatic potential after surgical removal of the primary murine fibrosarcoma , 1990, International journal of cancer.

[49]  F. Garrido,et al.  MHC antigens and malignancy. , 1986, Nature.

[50]  R. Schreiber,et al.  Demonstration of an interferon γ-dependent tumor surveillance system in immunocompetent mice , 1998 .

[51]  B. Seliger,et al.  Antigen-processing machinery breakdown and tumor growth. , 2000, Immunology today.

[52]  S. Pettit,et al.  Selection of metastatic tumour phenotypes by host immune systems , 1999, The Lancet.

[53]  A. McMichael,et al.  The epitopes of influenza nucleoprotein recognized by cytotoxic T lymphocytes can be defined with short synthetic peptides , 1986, Cell.

[54]  D. Geraghty,et al.  Analysis of HLA-E expression in human tumors , 2003, Immunogenetics.

[55]  S. Ferrone,et al.  Expression of histocompatibility (HLA) antigens on tumor cells and normal cells from patients with melanoma , 1977, Cancer.

[56]  Ian Tomlinson,et al.  Selection, the mutation rate and cancer: Ensuring that the tail does not wag the dog , 1999, Nature medicine.

[57]  F. Garrido,et al.  Analysis of HLA expression in human tumor tissues , 2002, Cancer Immunology, Immunotherapy.

[58]  F. Garrido,et al.  Characterization of a gastric tumor cell line defective in MHC class I inducibility by both alpha- and gamma-interferon. , 1996, Tissue Antigens.

[59]  D. Carbone,et al.  Structural and functional analysis of beta2 microglobulin abnormalities in human lung and breast cancer. , 1996, International Journal of Cancer.

[60]  F. Marincola,et al.  Escape of human solid tumors from T-cell recognition: molecular mechanisms and functional significance. , 2000, Advances in immunology.

[61]  K. Papadopoulos,et al.  MHC class I antigen processing pathways. , 1997, Human immunology.

[62]  F. Garrido,et al.  HLA and cancer: from research to clinical impact. , 1998, Immunology today.

[63]  F. Garrido,et al.  Immunoselection by T lymphocytes generates repeated MHC class I‐deficient metastatic tumor variants , 2001, International Journal of Cancer.

[64]  P. Stern,et al.  A mutation determining the loss of HLA-A2 antigen expression in a cervical carcinoma reveals novel splicing of human MHC class I classical transcripts in both tumoral and normal cells , 2000, Immunogenetics.

[65]  P. Klenerman,et al.  Immune surveillance against a solid tumor fails because of immunological ignorance. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[66]  J. Bodmer,et al.  Mechanisms of loss of HLA class I expression on colorectal tumor cells. , 1996, Tissue antigens.

[67]  P. Coulie,et al.  Characterization of an antigen that is recognized on a melanoma showing partial HLA loss by CTL expressing an NK inhibitory receptor. , 1997, Immunity.

[68]  G. Fleuren,et al.  Multiple Genetic Alterations Cause Frequent and Heterogeneous Human Histocompatibility Leukocyte Antigen Class I Loss in Cervical Cancer , 2000, The Journal of experimental medicine.

[69]  F. Garrido,et al.  High frequency of altered HLA class I phenotypes in invasive breast carcinomas. , 1996, Human immunology.

[70]  P. Stern,et al.  Multiple mechanisms underlie HLA dysregulation in cervical cancer. , 2000, Tissue Antigens.

[71]  P. van Endert.  Genes regulating MHC class I processing of antigen. , 1999, Current opinion in immunology.

[72]  F. Garrido,et al.  MHC antigens and tumor escape from immune surveillance. , 2001, Advances in cancer research.

[73]  S Ferrone,et al.  HLA class I antigen downregulation in human cancers: T-cell immunotherapy revives an old story. , 1999, Molecular medicine today.

[74]  A. Hill,et al.  MHC loss in colorectal tumours: evidence for immunoselection? , 1992, Cancer surveys.

[75]  M. Sanda,et al.  Molecular characterization of defective antigen processing in human prostate cancer. , 1995, Journal of the National Cancer Institute.

[76]  R. Biassoni,et al.  Receptors for HLA class-I molecules in human natural killer cells. , 1996, Annual review of immunology.

[77]  M. A. Saper,et al.  Structure of the human class I histocompatibility antigen, HLA-A2 , 1987, Nature.

[78]  H. Ljunggren,et al.  In search of the 'missing self': MHC molecules and NK cell recognition. , 1990, Immunology today.

[79]  J. Weissenbach,et al.  The beta2‐microglobulin mRNA in human Daudi cells has a mutated initiation codon but is still inducible by interferon. , 1983, The EMBO journal.

[80]  T. Ohta,et al.  Population Biology of Antigen Presentation by MHC Class I Molecules , 1996, Science.

[81]  A. Strasser,et al.  The great escape: Is immune evasion required for tumor progression? , 1999, Nature Medicine.

[82]  F. Real,et al.  Loss of an HLA haplotype in pancreas cancer tissue and its corresponding tumor derived cell line. , 1996, Tissue antigens.

[83]  S. Ferrone,et al.  Lack of HLA class I antigen expression by cultured melanoma cells FO-1 due to a defect in B2m gene expression. , 1991, The Journal of clinical investigation.

[84]  F. Garrido,et al.  High frequency of altered HLA class I phenotypes in laryngeal carcinomas. , 2000, Human immunology.

[85]  A. McMichael,et al.  Functions of nonclassical MHC and non-MHC-encoded class I molecules. , 1999, Current opinion in immunology.

[86]  H. Ljunggren,et al.  Chemically induced sarcomas from nude mice are more immunogenic than similar sarcomas from congenic normal mice , 1996, European journal of immunology.

[87]  F. Marincola,et al.  Selective Histocompatibility Leukocyte Antigen (Hla)-A2 Loss Caused by Aberrant Pre-mRNA Splicing in 624mel28 Melanoma Cells , 1999, The Journal of experimental medicine.

[88]  J. Zimmer,et al.  Analysis of natural killer cells in TAP2-deficient patients: expression of functional triggering receptors and evidence for the existence of inhibitory receptor(s) that prevent lysis of normal autologous cells. , 2002, Blood.

[89]  F. Garrido,et al.  Analysis of HLA class I expression in different metastases from two melanoma patients undergoing peptide immunotherapy. , 2001, Tissue antigens.

[90]  F. Garrido,et al.  Chromosome loss is the most frequent mechanism contributing to HLA haplotype loss in human tumors , 1999, International journal of cancer.

[91]  I. Svane,et al.  MCA Sarcomas Induced in scid Mice are More Immunogenic than MCA Sarcomas Induced in Congenic, Immunocompetent Mice , 1997, Scandinavian journal of immunology.

[92]  F. Oesch,et al.  Immunoselection in vivo: Independent loss of MHC class I and melanocyte differentiation antigen expression in metastatic melanoma , 1997, International journal of cancer.

[93]  S. Fuggle,et al.  THE DETAILED DISTRIBUTION OF HLA‐A, B, C ANTIGENS IN NORMAL HUMAN ORGANS , 1984, Transplantation.