Abstract
A remarkable advance in tumor immunology during the last decade is the elucidation of the antigenic basis of tumor recognition and destruction. A variety of tumor antigens have been identified using several strategies including conventional experiments and newly developed bioinformatics. Among these antigens, cancer/testis antigen (CT antigen) is considered to be the most promising target for immunotherapy by vaccination. Successful immunotherapy of tumors requires understanding of the natural relationship between the immune system and tumor in the status of differentiation, invasion and maturation. Continued progress in development of effective cancer vaccines depends on the identification of appropriate target antigens, the establishment of optimal immunization strategies without harmful autoimmune responses and the ability of manipulating tumor microenvironment to circumvent immune suppression and to augment the anti-tumor immune response.
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Prehn R T, Main J M. Immunity to methylcholanthrene-induced sarcomas. J Natl Cancer Inst, 1957, 18(6): 769–778
Klein G, Sjogren H O, Klein E, Hellstrom K E. Demonstration of resistance against methylcholanthrene-induced sarcomas in the primary autochthonous host. Cancer Res, 1960, 20: 1561–1572
Burnet F M. The concept of immunological surveillance. Prog Exp Tumor Res, 1970, 13: 1–27
Hewitt H B, Blake E R, Walder A S. A critique of the evidence for active host defence against cancer, based on personal studies of 27 murine tumours of spontaneous origin. Br J Cancer, 1976, 33(3): 241–259
Pardoll D. Does the immune system see tumors as foreign or self? Annu Rev Immunol, 2003, 21: 807–839
Woglom W H. Immunity to transplantable tumors. Cancer Res, 1929, 4: 129
Rosenberg S A. Progress in human tumour immunology and immunotherapy. Nature, 2001, 411(6835): 380–384
Van Pel A, Boon T. Protection against a nonimmunogenic mouse leukemia by an immunogenic variant obtained by mutagenesis. Proc Natl Acad Sci USA, 1982, 79(15): 4718–4722
Gilboa E. The makings of a tumor rejection antigen. Immunity, 1999, 11(3): 263–270
Hanahan D, Weinberg R A. The hallmarks of cancer. Cell, 2000, 100(1): 57–70
Giacomini C P, Leung S Y, Chen X, Yuen S T, Kim Y H, Bair E, Pollack J R. A gene expression signature of genetic instability in colon cancer. Cancer Res, 2005, 65(20): 9200–9205
Lengauer C, Kinzler K W, Vogelstein B. Genetic instabilities in human cancers. Nature, 1998, 396(6712): 643–649
De Smet C, Lurquin C, Lethe B, Martelange V, Boon T. DNA methylation is the primary silencing mechanism for a set of germ line-and tumor-specific genes with a CpG-rich promoter. Mol Cell Biol, 1999, 19(11): 7327–7335
Steinman R M, Mellman I. Immunotherapy bewitched, bothered, and bewildered no more. Science, 2004, 305(5681): 197–200
Morgan RA, Dudley ME, Wunderlich JR, Hughes MS, Yang JC, Sherry RM, Royal RE, Topalian SL, Kammula US, Restifo NP, Zheng Z, Nahvi A, de Vries CR, Rogers-Freezer LJ, Mavroukakis SA, Rosenberg SA. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science, 2006, 314(5796): 126–129
Hanson H L, Donermeyer D L, Ikeda H, White J M, Shankaran V, Old L J, Shiku H, Schreiber R D, Allen P M. Eradication of established tumors by CD8+ T cell adoptive immunotherapy. Immunity, 2000, 13(2): 265–276
Lopes L, Fletcher K, Ikeda Y, Collins M. Lentiviral vector expression of tumor antigens in dendritic cells as an immunotherapeutic strategy. Cancer Immunol Immunother, 2006, 55(8): 1011–1016
Asavaroengchai W, Kotera Y, Mule J J. Tumor lysate-pulsed dendritic cells can elicit an effective antitumor immune response during early lymphoid recovery. Proc Natl Acad Sci U S A, 2002, 99(2): 931–936
Gurunathan S, Wu C Y, Freidag B L, Seder RA. DNA vaccines: a key for inducing long-term cellular immunity. Curr Opin Immunol, 2000, 12(4): 442–447
Dudley M E, Rosenberg S A. Adoptive-cell-transfer therapy for the treatment of patients with cancer. Nat Rev Cancer, 2003, 3(9): 666–675
Jager E, Jager D, Knuth A. Clinical cancer vaccine trials. Curr Opin Immunol 2002, 14(2): 178–182
Robbins P F, El-Gamil M, Li Y F, Fitzgerald E B, Kawakami Y, Rosenberg S A. The intronic region of an incompletely spliced gp 100 gene transcript encodes an epitope recognized by melanoma-reactive tumor-infiltrating lymphocytes. J Immunol, 1997, 159(1): 303–308
Robbins P F, El-Gamil M, Li Y F, Kawakami Y, Loftus D, Appella E, Rosenberg S A. A mutated beta-catenin gene encodes a melanoma-specific antigen recognized by tumor infiltrating lymphocytes. J Exp Med, 1996, 183(3): 1185–1192
Robbins P F, el-Gamil M, Li Y F, Topalian S L, Rivoltini L, Sakaguchi K, Appella E, Kawakami Y, Rosenberg S A. Cloning of a new gene encoding an antigen recognized by melanoma-specific HLA-A24-restricted tumor-infiltrating lymphocytes. J Immunol, 1995, 154(11): 5944–5950
Wang R F, Johnston S L, Zeng G, Topalian S L, Schwartzentruber D J, Rosenberg S A. A breast and melanoma-shared tumor antigen: T cell responses to antigenic peptides translated from different open reading frames. J Immunol, 1998, 161(7): 3598–3606
Boon T, Cerottini J C, Van den Eynde B, van der Bruggen P, Van Pel A. Tumor antigens recognized by T lymphocytes. Annu Rev Immunol, 1994, 12: 337–365
Mizukoshi E, Nakamoto Y, Marukawa Y, Arai K, Yamashita T, Tsuji H, Kuzushima K, Takiguchi M, Kaneko S. Cytotoxic T cell responses to human telomerase reverse transcriptase in patients with hepatocellular carcinoma. Hepatology, 2006, 43(6): 1284–1294
Marzo A L, Kinnear B F, Lake R A, Frelinger J J, Collins E J, Robinson B W, Scott B. Tumor-specific CD4+ T cells have a major “post-licensing” role in CTL mediated anti-tumor immunity. J Immunol, 2000, 165(11): 6047–6055
Sun J C, Bevan M J. Defective CD8 T cell memory following acute infection without CD4 T cell help. Science, 2003, 300(5617): 339–342
Shedlock D J, Shen H. Requirement for CD4 T cell help in generating functional CD8 T cell memory. Science, 2003, 300(5617): 337–339
Rosenberg S A, Yang J C, Restifo N P. Cancer immunotherapy moving beyond current vaccines. Nat Med, 2004, 10(9): 909–915
Qin Z, Richter G, Schuler T, Ibe S, Cao X, Blankenstein T. B cells inhibit induction of T cell-dependent tumor immunity. Nat Med, 1998, 4(5): 627–630
Hara I, Takechi Y, Houghton A N. Implicating a role for immune recognition of self in tumor rejection passive immunization against the brown locus protein. J Exp Med, 1995, 182(5): 1609–1614
Renkvist N, Castelli C, Robbins P F, Parmiani G. A listing of human tumor antigens recognized by T cells. Cancer Immunol Immunother, 2001, 50(1): 3–15
Knuth A, Boon T. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science, 1991, 254(5038): 1643–1647
Boel P, Wildmann C, Sensi M L, Brasseur R, Renauld J C, Coulie P, Boon T, van der Bruggen P. BAGE a new gene encoding an antigen recognized on human melanomas by cytolytic T lymphocytes. Immunity, 1995, 2(2): 167–175
Van den Eynde B, Peeters O, De Backer O, Gaugler B, Lucas S, Boon T. A new family of genes coding for an antigen recognized by autologous cytolytic T lymphocytes on a human melanoma. J Exp Med, 1995, 182(3): 689–698
Rosenberg S A. A new era for cancer immunotherapy based on the genes that encode cancer antigens. Immunity, 1999, 10(3): 281–287
Mandelboim O, Berke G, Fridkin M, Feldman M, Eisenstein M, Eisenbach L. CTL induction by a tumour-associated antigen octapeptide derived from a murine lung carcinoma. Nature, 1994, 369(6475): 67–71
Hunt D F, Henderson R A, Shabanowitz J, Sakaguchi K, Michel H, Sevilir N, Cox A L, Appella E, Engelhard V H. Characterization of peptides bound to the class I MHC molecule HLA-A2 1 by mass spectrometry. Science, 1992, 255(5049): 1261–1263
Cox A L, Skipper J, Chen Y, Henderson R A, Darrow T L, Shabanowitz J, Engelhard V H, Hunt D F, Slingluff C L Jr. Identification of a peptide recognized by five melanoma-specific human cytotoxic T cell lines. Science, 1994, 264(5159): 716–719
Sahin U, Tureci O, Schmitt H, Cochlovius B, Johannes T, Schmits R, Stenner F, Luo G, Schobert I, Pfreundschuh M. Human neoplasms elicit multiple specific immune responses in the autologous host. Proc Natl Acad Sci U S A, 1995, 92(25): 11810–11813
Scanlan M J, Gout I, Gordon C M, Williamson B, Stockert E, Gure A O, Jager D, Chen Y T, Mackay A, O’Hare M J, Old L J. Humoral immunity to human breast cancer: antigen definition and quantitative analysis of mRNA expression. Cancer Immun, 2001, 1:4
Wang Y, Han K J, Pang X W, Vaughan H A, Qu W, Dong X Y, Peng J R, Zhao H T, Rui J A, Leng X S, Cebon J, Burgess A W, Chen W F. Large scale identification of human hepatocellular carcinoma-associated antigens by autoantibodies. J Immunol, 2002, 169(2): 1102–1109
Li B, Qian X P, Pang X W, Zou W Z, Wang Y P, Wu H Y, Chen W F. HCA587 antigen expression in normal tissues and cancers: correlation with tumor differentiation in hepatocellular carcinoma. Lab Invest, 2003, 83(8): 1185–1192
Li B, Wu H Y, Qian X P, Li Y, Chen W F. Expression, purification and serological analysis of hepatocellular carcinoma associated antigen HCA587 in insect cells. World J Gastroenterol, 2003, 9(4): 678–682
Li B, He X, Pang X, Zhang H, Chen J, Chen W. Elicitation of both CD4 and CD8 T-cell-mediated specific immune responses to HCA587 protein by autologous dendritic cells. Scand J Immunol, 2004, 60(5): 506–513
Li B, Wang Y, Chen J, Wu H, Chen W. Identification of a new HLA-A*0201-restricted CD8+ T cell epitope from hepatocellular carcinoma-associated antigen HCA587. Clin Exp Immunol. 2005, 140(2): 310–319
Shi Y Y, Wang H C, Yin Y H, Sun W S, Li Y, Zhang C Q, Wang Y, Wang S, Chen W F. Identification and analysis of tumour-associated antigens in hepatocellular carcinoma. Br J Cancer, 2005, 92(5): 929–934
Cho B, Lim Y, Lee D Y, Park S Y, Lee H, Kim W H, Yang H, Bang Y J, Jeoung D I. Identification and characterization of a novel cancer/testis antigen gene CAGE. Biochem Biophys Res Commun, 2002, 292(3): 715–726
Chen Y T. Identification of human tumor antigens by serological expression cloning: an online review on SEREX. Cancer Immun 2004 [updated 2004 Mar 10; cited 2004 Apr 1] URL: http://www.cancerimmunity.org/SEREX/
Davis I D, Jefford M, Parente P, Cebon J. Rational approaches to human cancer immunotherapy. J Leukoc Biol, 2003, 73(1): 3–29
Antonia S, Mule J J, Weber J S. Current developments of immunotherapy in the clinic. Curr Opin Immunol, 2004, 16(2): 130–136
Lucas S, De Smet C, Arden K C, Viars C S, Lethe B, Lurquin C, Boon T. Identification of a new MAGE gene with tumor-specific expression by representational difference analysis. Cancer Res, 1998, 58(4): 743–752
Dong X Y, Pang X W, Yu S T, Su Y R, Wang H C, Yin Y H, Wang Y D, Chen W F. Identification of genes differentially expressed in human hepatocellular carcinoma by a modified suppression subtractive hybridization method. Int J Cancer, 2004, 112(2): 239–248
Yoshitake Y, Nakatsura T, Monji M, Senju S, Matsuyoshi H, Tsukamoto H, Hosaka S, Komori H, Fukuma D, Ikuta Y, Katagiri T, Furukawa Y, Ito H, Shinohara M, Nakamura Y, Nishimura Y. Proliferation potential-related protein, an ideal esophageal cancer antigen for immunotherapy, identified using complementary DNA microarray analysis. Clin Cancer Res, 2004, 10(19): 6437–6448
Wang X, Zhao H, Xu Q, Jin W, Liu C, Zhang H, Huang Z, Zhang X, Zhang Y, Xin D, Simpson A J, Old L J, Na Y, Zhao Y, Chen W. HPtaa database-potential target genes for clinical diagnosis and immunotherapy of human carcinoma. Nucleic Acids Res, 2006, 34(Database issue): D607–D612
Cavallo F, Astolfi A, Iezzi M, Cordero F, Lollini P L, Fomi G, Calogero R. An integrated approach of immunogenomics and bioinformatics to identify new Tumor Associated Antigens (TAA) for mammary cancer immunological prevention. BMC Bioinformatics, 2005, 6(Suppl 4): S7
Dopazo J. Bioinformatics and cancer: an essential alliance. Clin Transl Oncol, 2006; 8(6): 409–415
Hermeking H. Serial analysis of gene expression and cancer. Curr Opin Oncol, 2003, 15(1): 44–49
Chen Y T, Scanlan M J, Venditti C A, Chua R, Theiler G, Stevenson B J, Iseli C, Gure A O, Vasicek T, Strausberg R L, Jongeneel C V, Old L J, Simpson A J. Identification of cancer/testis-antigen genes by massively parallel signature sequencing. Proc Natl Acad Sci U S A, 2005, 102(22): 7940–7945
Jongeneel C V, Iseli C, Stevenson B J, Riggins G J, Lal A, Mackay A, Harris R A, O’Hare M J, Neville A M, Simpson A J, Strausberg R L. Comprehensive sampling of gene expression in human cell lines with massively parallel signature sequencing. Proc Natl Acad Sci U S A, 2003, 100(8): 4702–4705
Dong X Y, Su Y R, Qian X P, Yang X A, Pang X W, Wu H Y, Chen W F. Identification of two novel CT antigens and their capacity to elicit antibody response in hepatocellular carcinoma patients, Br J Cancer, 2003, 89(2): 291–297
Dong X Y, Yang X A, Wang Y D, Chen W F. Zinc-finger protein ZNF165 is a novel cancer-testis antigen capable of eliciting antibody response in hepatocellular carcinoma patients. Br J Cancer, 2004, 91(8): 1566–1570
Dong X Y, Li Y Y, Yang X A, Chen W F. BJ-HCC-20, a potential novel cancer-testis antigen. Biochem Cell Biol, 2004, 82(5): 577–582
Li Y, Dong X, Yin Y, Su Y, Xu Q, Zhang Y, Pang X, Zhang Y, Chen W. BJ-TSA-9, a novel human tumor-specific gene, has potential as a biomarker of lung cancer. Neoplasia, 2005, 7(12): 1073–1080
Wang X S, Zhang Z, Wang H C, Cai J L, Xu Q W, Li M Q, Chen Y C, Qian X P, Lu T J, Yu L Z, Zhang Y, Xin D Q, Na Y Q, Chen W F. Rapid identification of UCA1 as a very sensitive and specific unique marker for human bladder carcinoma. Clin Cancer Res, 2006, 12(16): 4851–4858
Letsch A, Scheibenbogen C. Quantification and characterization of specific T-cells by antigen-specific cytokine production using ELISPOT assay or intracellular cytokine staining. Methods, 2003, 31(2): 143–149
Yee C, Greenberg P. Modulating T-cell immunity to tumours: new strategies for monitoring T-cell responses. Nat Rev Cancer, 2002, 2(6): 409–419
Simon R M, Steinberg S M, Hamilton M, Hildesheim A, Khleif S, Kwak L W, Mackall C L, Schlom J, Topalian S L, Berzofsky J A. Clinical trial designs for the early clinical development of therapeutic cancer vaccines. J Clin Oncol, 2001, 19(6): 1848–1854
Scanlan M J, Gure A O, Jungbluth A A, Old L J, Chen Y T. Cancer/testis antigens: an expanding family of targets for cancer immunotherapy. Immunol Rev, 2002, 188: 22–32
Kan T, Yamasaki S, Kondo K, Teratani N, Kawabe A, Kaganoi J, Meltzer S J, Imamura M, Shimada Y. A new specific gene expression in squamous cell carcinoma of the esophagus detected using representational difference analysis and cDNA microarray. Oncology, 2006, 70(1): 25–33
Gilboa E. The promise of cancer vaccines. Nat Rev Cancer, 2004, 4(5): 401–411
Steinman R M, Hawiger D, Nussenzweig M C. Tolerogenic dendritic cells. Annu Rev Immunol, 2003, 21: 685–711
Hodi F S, Dranoff G. Combinatorial cancer immunotherapy. Adv Immunol, 2006, 90: 341–368
Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu Y J, Pulendran B, Palucka K. Immunobiology of dendritic cells. Annu Rev Immunol, 2000, 18: 767–811
Jego G, Palucka A K, Blanck J P, Chalouni C, Pascual V, Banchereau J. Plasmacytoid dendritic cells induce plasma cell differentiation through type I interferon and interleukin 6. Immunity, 2003, 19(2): 225–234
Banchereau J, Palucka A K. Dendritic cells as therapeutic vaccines against cancer. Nat Rev Immunol, 2005, 5(4): 296–306
Ojima T, Iwahashi M, Nakamura M, Matsuda K, Naka T, Nakamori M, Ueda K, Ishida K, Yamaue H. The boosting effect of co-transduction with cytokine genes on cancer vaccine therapy using genetically modified dendritic cells expressing tumor-associated antigen. Int J Oncol, 2006, 28(4): 947–953
Figdor C G, de Vries I J, Lesterhuis W J, Melief C J. Dendritic cell immunotherapy mapping the way. Nat Med, 2004, 10(5): 475–480
Fong L, Engleman E G. Dendritic cells in cancer immunotherapy. Annu Rev Immunol, 2000, 18: 245–273
Yang L, Carbone D P. Tumor-host immune interactions and dendritic cell dysfunction. Adv Cancer Res, 2004, 92: 13–27
Biragyn A, Surenhu M, Yang D, Ruffini P A, Haines B A, Klyushnenkova E, Oppenheim J J, Kwak L W. Mediators of innate immunity that target immature, but not mature, dendritic cells induce antitumor immunity when genetically fused with nonimmunogenic tumor antigens. J Immunol, 2001, 167(11): 6644–6653
You Z, Huang X, Hester J, Toh H C, Chen S Y. Targeting dendritic cells to enhance DNA vaccine potency. Cancer Res, 2001, 61(9): 3704–3711
de Gruijl T D, Luykx-de Bakker S A, Tillman B W, van den Eertwegh A J. Prolonged maturation and enhanced transduction of dendritic cells migrated from human skin explants after in situ delivery of CD40-targeted adenoviral vectors. J Immunol, 2002, 169(9): 5322–5331
den Brok M H, Sutmuller R P, Nierkens S, Bennink E J, Toonen L W, Figdor C G, Ruers T J, Adema G J. Synergy between in situ cryoablation and TLR9 stimulation results in a highly effective in vivo dendritic cell vaccine. Cancer Res, 2006, 66(14): 7285–7292
Pinzon-Charry A, Maxwell T, McGuckin MA, Schmidt C, Fumival C, Lopez J A. Spontaneous apoptosis of blood dendritic cells in patients with breast cancer. Breast Cancer Res, 2006, 8(1): R5
Markiewicz M A, Kast W M. Progress in the development of immunotherapy of cancer using ex vivo-generated dendritic cells expressing multiple tumor antigen epitopes. Cancer Invest, 2004, 22(3): 417–434
Hiraoka K, Yamamoto S, Otsuru S, Nakai S, Tamai K, Morishita R, Ogihara T, Kaneda Y. Enhanced tumor-specific long-term immunity of hemagglutinating [correction of hemaggluttinating] virus of Japan-mediated dendritic cell-tumor fused cell vaccination by coadministration with CpG oligodeoxynucleotides. J Immunol, 2004, 173(7): 4297–4307
Mora J R, Bono M R, Manjunath N, Weninger W, Cavanagh L L, Rosemblatt M, Von Andrian U H. Selective imprinting of gut-homing T cells by Peyer’s patch dendritic cells. Nature, 2003, 424(6944): 88–93
Mullins D W, Sheasley S L, Ream R M, Bullock T N, Fu Y X, Engelhard V H. Route of immunization with peptide-pulsed dendritic cells controls the distribution of memory and effector T cells in lymphoid tissues and determines the pattern of regional tumor control. J Exp Med, 2003, 198(7): 1023–1034
Shevach E M. CD4+ CD25+ suppressor T cells more questions than answers. Nat Rev Immunol, 2002, 2(6): 389–400
von Herrath M G, Harrison L C. Antigen-induced regulatory T cells in autoimmunity. Nat Rev Immunol, 2003, 3(3): 223–232
Sakaguchi S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol, 2005, 6(4): 345–352
Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science, 2003, 299(5609): 1057–1061
McHugh R S, Whitters M J, Piccirillo C A, Young D A, Shevach E M, Collins M, Byme M C. CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity, 2002, 16(2): 311–323
Awwad M, North R J. Cyclophosphamide (Cy)-facilitated adoptive immunotherapy of a Cy-resistant tumour: Evidence that Cy permits the expression of adoptive T-cell mediated immunity by removing suppressor T cells rather than by reducing tumour burden. Immunology, 1988, 65(1): 87–92
Sutmuller R P, van Duivenvoorde L M, van Elsas A, Schumacher T N, Wildenberg M E, Allison J P, Toes R E, Offringa R, Melief C J. Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25(+) regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses. J Exp Med, 2001, 194(6): 823–832
Mocellin S, Wang E, Marincola F M. Cytokines and Immune Response in the Tumor Microenvironment. J Immunother, 2001, 24(5): 392–407
Broderick L, Bankert R B. Membrane-Associated TGF-beta1 Inhibits Human Memory T Cell Signaling in Malignant and Nonmalignant Inflammatory Microenvironments. J Immunol, 2006, 177(5): 3082–3088
Bierie B, Moses H L. Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer. Nat Rev Cancer, 2006, 6(7): 506–520
Kitano H. Cancer robustness: tumour tactics. Nature, 2003, 426(6963): 125
Kitano H. Systems biology a brief overview. Science, 2002, 295(5560): 1662–1664
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Xu, Q., Chen, W. Developing effective tumor vaccines: basis, challenges and perspectives. Front. Med. China 1, 11–19 (2007). https://doi.org/10.1007/s11684-007-0003-9
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DOI: https://doi.org/10.1007/s11684-007-0003-9