Download PDF
Aktuelle Urol 2004; 35(4): 326-330
DOI: 10.1055/s-2004-818510
Klinische Originalarbeit
© Georg Thieme Verlag Stuttgart · New York

Adaptive Immuntherapie des fortgeschrittenen Prostatakarzinoms - Cancer Testis Antigene (CTA) als mögliche Zielantigene

Adaptive Immunotherapy of the Advanced Prostate Cancer - Cancer Testis Antigen (CTA) as Possible Target AntigensL.  Prikler1 , E.  Scandella2 , Y.  Men2 , D.  S.  Engeler1 , P.-A.  Diener4 , S.  Gillessen3 , B.  Ludewig2 , H.-P.  Schmid1
  • 1Klinik für Urologie, CH-St. Gallen
  • 2Laborforschungsabteilung, CH-St. Gallen
  • 3Klinik für Onkologie, CH-St. Gallen
  • 4Institut für Pathologie, Kantonsspital CH-St. Gallen
Further Information

Publication History

Publication Date:
27 August 2004 (online)

Also available at
    Permissions and Reprints

Zusammenfassung

Das Prostatakarzinom (PCa) wie auch andere Tumoren exprimieren Antigene, die als Angriffspunkte für eine spezifische Immuntherapie dienen können. Spezielle antigenpräsentierende Zellen (z. B. dendritische Zellen) bieten dabei dem Immunsystem die Antigene an, so dass eine entsprechende Antwort ausgelöst wird. Sehr effektiv gehen dabei zytotoxische T-Zellen (sog. Killerzellen) gegen die Antigene und somit gegen das entsprechende Gewebe respektive den Tumor vor. Cancer Testis Antigene (CTA) werden in verschiedenen menschlichen Karzinomen exprimiert, außer im Hoden aber nicht in normalem Gewebe. Sie eignen sich damit ideal für eine spezifische Tumor-Immuntherapie. Wir untersuchten, ob einige dieser CTA (LAGE-1, PRAME, MAGE-C2, NY-ESO-1, SSX-2 und PAGE4) auch im Prostatakarzinom vorkommen. Dabei zeigte sich eine sehr heterogene Expression der CTA in verschiedenen PCa-Zelllinien oder PCa-Proben aus unserem Patientengut. Nur PAGE4 wies neben einer Expression in primären PCa und LnCaP-Zellen auch eine Expression in hormonabhängigen und -refraktären PCa-Proben auf, so dass es als mögliches Zielantigen zur Immuntherapie des PCa weiter evaluiert wird.

Abstract

Prostate cancer (PCa) like other tumors expresses antigens that may serve as target for specific immunotherapy. Special antigen-presenting cells (e. g., dendritic cells) are capable of generating tumor-specific immunity. Cytotoxic T-cells (killer cells) are very effective against antigens and, consequently, against the respective tissue or tumor. Cancer testis antigens (CTA) are expressed in various human cancers but, aside from the testicles, not in normal tissue. Therefore, they are suitable for a specific tumor immunotherapy. We looked at different CTA (LAGE-1, PRAME, MAGE-C2, NY-ESO-1, SSX-2 and PAGE4) and their occurrence in prostatic cancer. Expression of CTA in various PCa cell lines and PCa material from patients was very heterogeneous. Only PAGE4 was expressed in primary PCa and in LnCaP cells as well as in hormone-dependent and hormone-refractory PCa probes. We conclude that PAGE4 should be further evaluated as a potential target for immunotherapy of PCa.

Schlüsselwörter

Prostatakarzinom - Immuntherapie - Cancer Testis Antigen - dendritische Zellen

Key words

Prostatic cancer - immunotherapy - cancer testis antigens - dendritic cells

Literatur

  • 1 Ashley D M, Faiola B, Nair S, Hale L P, Bigner D D, Gilboa E. Bone marrow-generated dendritic cells pulsed with tumor extracts or tumor RNA induce antitumor immunity against central nervous system tumors.  J Exp Med. 1997;  186 (7) 1177-1182
    CrossrefPubMedGoogle Scholar
  • 2 Austyn J M, Hankins D F, Larsen C P, Morris P J, Rao A S, Roake J A. Isolation and characterization of dendritic cells from mouse heart and kidney.  J Immunol. 1994;  152 (5) 2401-2410
    PubMedGoogle Scholar
  • 3 Banchereau J, Steinman R M. Dendritic cells and the control of immunity.  Nature. 1998;  392 (6673) 245-252
    CrossrefPubMedGoogle Scholar
  • 4 Banchereau J, Schuler-Thurner B, Palucka A K, Schuler G. Dendritic cells as vectors for therapy.  Cell. 2001;  106 (3) 271-274
    CrossrefPubMedGoogle Scholar
  • 5 Boczkowski D, Nair S K, Snyder D, Gilboa E. Dendritic cells pulsed with RNA are potent antigen-presenting cells in vitro and in vivo.  J Exp Med. 1996;  184 (2) 465-472
    CrossrefPubMedGoogle Scholar
  • 6 Brinkmann U, Vasmatzis G, Lee B, Yerushalmi N, Essand M, Pastan I. PAGE-1, an X chromosome-linked GAGE-like gene that is expressed in normal and neoplastic prostate, testis, and uterus.  Proc Natl Acad Sci U S A. 1998;  95 (18) 10 757-10 762
    PubMedGoogle Scholar
  • 7 Brossart P, Zobywalski A, Grunebach F, Behnke L, Stuhler G, Reichardt V L, Kanz L, Brugger W. Tumor necrosis factor alpha and CD40 ligand antagonize the inhibitory effects of interleukin 10 on T-cell stimulatory capacity of dendritic cells.  Cancer Res. 2000;  60 (16) 4485-4492
    PubMedGoogle Scholar
  • 8 Cella M, Engering A, Pinet V, Pieters J, Lanzavecchia A. Inflammatory stimuli induce accumulation of MHC class II complexes on dendritic cells.  Nature. 1997;  388 (6644) 782-787
    CrossrefPubMedGoogle Scholar
  • 9 Dannull J, Diener P A, Prikler L, Furstenberger G, Cerny T, Schmid U, Ackermann D K, Groettrup M. Prostate stem cell antigen is a promising candidate for immunotherapy of advanced prostate cancer.  Cancer Res. 2000;  60 (19) 5522-5528
    PubMedGoogle Scholar
  • 10 Dutoit V, Taub R N, Papadopoulos K P, Talbot S, Keohan M L, Brehm M, Gnjatic S, Harris P E, Bisikirska B, Guillaume P. et al . Multiepitope CD8(+) T cell response to a NY-ESO-1 peptide vaccine results in imprecise tumor targeting.  J Clin Invest. 2002;  110 (12) 1813-1822
    CrossrefPubMedGoogle Scholar
  • 11 Eder J P, Kantoff P W, Roper K, Xu G X, Bubley G J, Boyden J, Gritz L, Mazzara G, Oh W K, Arlen P. et al . A phase I trial of a recombinant vaccinia virus expressing prostate-specific antigen in advanced prostate cancer.  Clin Cancer Res. 2000;  6 (5) 1632-1638
    PubMedGoogle Scholar
  • 12 Flamand V, Sornasse T, Thielemans K, Demanet C, Bakkus M, Bazin H, Tielemans F, Leo O, Urbain J, Moser M. Murine dendritic cells pulsed in vitro with tumor antigen induce tumor resistance in vivo.  Eur J Immunol. 1994;  24 (3) 605-610
    PubMedGoogle Scholar
  • 13 Fong L, Engleman E G. Dendritic cells in cancer immunotherapy.  Annu Rev Immunol. 2000;  18 245-273
    CrossrefPubMedGoogle Scholar
  • 14 Hsu F J, Benike C, Fagnoni F, Liles T M, Czerwinski D, Taidi B, Engleman E G, Levy R. Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed dendritic cells.  Nat Med. 1996;  2 (1) 52-58
    PubMedGoogle Scholar
  • 15 Iavarone C, Wolfgang C, Kumar V, Duray P, Willingham M, Pastan I, Bera T K. PAGE4 is a cytoplasmic protein that is expressed in normal prostate and in prostate cancers.  Mol Cancer Ther. 2002;  1 (5) 329-335
    PubMedGoogle Scholar
  • 16 La Motte R N, Sharpe A H, Bluestone J A, Mokyr M B. Host B7 - 1 and B7 - 2 costimulatory molecules contribute to the eradication of B7 - 1-transfected P815 tumor cells via a CD8+ T cell-dependent mechanism.  J Immunol. 1999;  162 (8) 4817-4823
    PubMedGoogle Scholar
  • 17 Ludewig B, McCoy K, Pericin M, Ochsenbein A F, Dumrese T, Odermatt B, Toes R E, Melief C J, Hengartner H, Zinkernagel R M. Rapid peptide turnover and inefficient presentation of exogenous antigen critically limit the activation of self-reactive CTL by dendritic cells.  J Immunol. 2001;  166 (6) 3678-3687
    PubMedGoogle Scholar
  • 18 Mach N, Dranoff G. Cytokine-secreting tumor cell vaccines.  Curr Opin Immunol. 2000;  12 (5) 571-575
    PubMedGoogle Scholar
  • 19 Mincheff M, Tchakarov S, Zoubak S, Loukinov D, Botev C, Altankova I, Georgiev G, Petrov S, Meryman H T. Naked DNA and adenoviral immunizations for immunotherapy of prostate cancer: a phase I/II clinical trial.  Eur Urol. 2000;  38 (2) 208-217
    CrossrefPubMedGoogle Scholar
  • 20 Morant R, Hsu Schmitz S F, Bernhard J, Thurlimann B, Borner M, Wernli M, Egli F, Forrer P, Streit A, Jacky E. et al . Vinorelbine in androgen-independent metastatic prostatic carcinoma - a phase II study.  Eur J Cancer. 2002;  38 (12) 1626-1632
    CrossrefPubMedGoogle Scholar
  • 21 Muller S, Hanisch F G. Recombinant MUC1 probe authentically reflects cell-specific O-glycosylation profiles of endogenous breast cancer mucin. High density and prevalent core 2-based glycosylation.  J Biol Chem. 2002;  277 (29) 26 103-26 112
    PubMedGoogle Scholar
  • 22 Nair S K, Boczkowski D, Morse M, Cumming R I, Lyerly H K, Gilboa E. Induction of primary carcinoembryonic antigen (CEA)-specific cytotoxic T lymphocytes in vitro using human dendritic cells transfected with RNA.  Nat Biotechnol. 1998;  16 (4) 364-369
    PubMedGoogle Scholar
  • 23 Nestle F O, Alijagic S, Gilliet M, Sun Y, Grabbe S, Dummer R, Burg G, Schadendorf D. Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells.  Nat Med. 1998;  4 (3) 328-332
    PubMedGoogle Scholar
  • 24 Nestle F O. Dendritic cell vaccination for cancer therapy.  Oncogene. 2000;  19 (56) 6673-6679
    CrossrefPubMedGoogle Scholar
  • 25 Ochsenbein A F, Klenerman P, Karrer U, Ludewig B, Pericin M, Hengartner H, Zinkernagel R M. Immune surveillance against a solid tumor fails because of immunological ignorance.  Proc Natl Acad Sci U S A. 1999;  96 (5) 2233-2238
    PubMedGoogle Scholar
  • 26 Ochsenbein A F, Sierro S, Odermatt B, Pericin M, Karrer U, Hermans J, Hemmi S, Hengartner H, Zinkernagel R M. Roles of tumour localization, second signals and cross priming in cytotoxic T-cell induction.  Nature. 2001;  411 (6841) 1058-1064
    CrossrefPubMedGoogle Scholar
  • 27 Ossevoort M A, Feltkamp M C, Veen K J van, Melief C J, Kast W M. Dendritic cells as carriers for a cytotoxic T-lymphocyte epitope-based peptide vaccine in protection against a human papillomavirus type 16-induced tumor.  J Immunother Emphasis Tumor Immunol. 1995;  18 (2) 86-94
    PubMedGoogle Scholar
  • 28 Pantuck A J vOA, Gitlitz B J. et al . MUC-1-IL-2 gene therapy for advanced prostate cancer: phase I trial and clinical response associated systemic immune activation (abstract).  J Urol. 2000;  163(suppl) 158
    PubMedGoogle Scholar
  • 29 Pardoll D M. Cancer vaccines.  Nat Med. 1998;  4 (5 Suppl) 525-531
    PubMedGoogle Scholar
  • 30 Pardoll D M. Spinning molecular immunology into successful immunotherapy.  Nat Rev Immunol. 2002;  2 (4) 227-238
    CrossrefPubMedGoogle Scholar
  • 31 Pierre P, Turley S J, Gatti E, Hull M, Meltzer J, Mirza A, Inaba K, Steinman R M, Mellman I. Developmental regulation of MHC class II transport in mouse dendritic cells.  Nature. 1997;  388 (6644) 787-792
    CrossrefPubMedGoogle Scholar
  • 32 Rea D, Havenga M J, Assem M van Den, Sutmuller R P, Lemckert A, Hoeben R C, Bout A, Melief C J, Offringa R. Highly efficient transduction of human monocyte-derived dendritic cells with subgroup B fiber-modified adenovirus vectors enhances transgene-encoded antigen presentation to cytotoxic T cells.  J Immunol. 2001;  166 (8) 5236-5244
    PubMedGoogle Scholar
  • 33 Reis e Sousa C, Stahl P D, Austyn J M. Phagocytosis of antigens by Langerhans cells in vitro.  J Exp Med. 1993;  178 (2) 509-519
    CrossrefPubMedGoogle Scholar
  • 34 Romani N, Koide S, Crowley M, Witmer-Pack M, Livingstone A M, Fathman C G, Inaba K, Steinman R M. Presentation of exogenous protein antigens by dendritic cells to T cell clones. Intact protein is presented best by immature, epidermal Langerhans cells.  J Exp Med. 1989;  169 (3) 1169-1178
    CrossrefPubMedGoogle Scholar
  • 35 Romani N, Gruner S, Brang D, Kampgen E, Lenz A, Trockenbacher B, Konwalinka G, Fritsch P O, Steinman R M, Schuler G. Proliferating dendritic cell progenitors in human blood.  J Exp Med. 1994;  180 (1) 83-93
    CrossrefPubMedGoogle Scholar
  • 36 Rosenberg S A, Spiess P, Lafreniere R. A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes.  Science. 1986;  233 (4770) 1318-1321
    PubMedGoogle Scholar
  • 37 Sadanaga N, Nagashima H, Mashino K, Tahara K, Yamaguchi H, Ohta M, Fujie T, Tanaka F, Inoue H, Takesako K. et al . Dendritic cell vaccination with MAGE peptide is a novel therapeutic approach for gastrointestinal carcinomas.  Clin Cancer Res. 2001;  7 (8) 2277-2284
    PubMedGoogle Scholar
  • 38 Sallusto F, Lanzavecchia A. Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha.  J Exp Med. 1994;  179 (4) 1109-1118
    CrossrefPubMedGoogle Scholar
  • 39 Sallusto F, Cella M, Danieli C, Lanzavecchia A. Dendritic cells use macropinocytosis and the mannose receptor to concentrate macromolecules in the major histocompatibility complex class II compartment: downregulation by cytokines and bacterial products.  J Exp Med. 1995;  182 (2) 389-400
    CrossrefPubMedGoogle Scholar
  • 40 Sanda M G, Ayyagari S R, Jaffee E M, Epstein J I, Clift S L, Cohen L K, Dranoff G, Pardoll D M, Mulligan R C, Simons J W. Demonstration of a rational strategy for human prostate cancer gene therapy.  J Urol. 1994;  151 (3) 622-628
    PubMedGoogle Scholar
  • 41 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
    CrossrefPubMedGoogle Scholar
  • 42 Scholfield D P, Simms M S, Bishop M C. MUC1 mucin in urological malignancy.  BJU Int. 2003;  91 (6) 560-566
    CrossrefPubMedGoogle Scholar
  • 43 Simons J W, Mikhak B, Chang J F, DeMarzo A M, Carducci M A, Lim M, Weber C E, Baccala A A, Goemann M A, Clift S M. et al . Induction of immunity to prostate cancer antigens: results of a clinical trial of vaccination with irradiated autologous prostate tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor using ex vivo gene transfer.  Cancer Res. 1999;  59 (20) 5160-5168
    PubMedGoogle Scholar
  • 44 Slingluff C L. Targeting unique tumor antigens and modulating the cytokine environment may improve immunotherapy for tumors with immune escape mechanisms.  Cancer Immunol Immunother. 1999;  48 (7) 371-373
    PubMedGoogle Scholar
  • 45 Song W, Kong H L, Carpenter H, Torii H, Granstein R, Rafii S, Moore M A, Crystal R G. Dendritic cells genetically modified with an adenovirus vector encoding the cDNA for a model antigen induce protective and therapeutic antitumor immunity.  J Exp Med. 1997;  186 (8) 1247-1256
    CrossrefPubMedGoogle Scholar
  • 46 Specht J M, Wang G, Do M T, Lam J S, Royal R E, Reeves M E, Rosenberg S A, Hwu P. Dendritic cells retrovirally transduced with a model antigen gene are therapeutically effective against established pulmonary metastases.  J Exp Med. 1997;  186 (8) 1213-1221
    CrossrefPubMedGoogle Scholar
  • 47 Steinman R M, Pope M. Exploiting dendritic cells to improve vaccine efficacy.  J Clin Invest. 2002;  109 (12) 1519-1526
    CrossrefPubMedGoogle Scholar
  • 48 Wang R F, Rosenberg S A. Human tumor antigens for cancer vaccine development.  Immunol Rev. 1999;  170 85-100
    PubMedGoogle Scholar
  • 49 Wick M, Dubey P, Koeppen H, Siegel C T, Fields P E, Chen L, Bluestone J A, Schreiber H. Antigenic cancer cells grow progressively in immune hosts without evidence for T cell exhaustion or systemic anergy.  J Exp Med. 1997;  186 (2) 229-238
    CrossrefPubMedGoogle Scholar
  • 50 Zinkernagel R M, Ehl S, Aichele P, Oehen S, Kundig T, Hengartner H. Antigen localisation regulates immune responses in a dose- and time-dependent fashion: a geographical view of immune reactivity.  Immunol Rev. 1997;  156 199-209
    CrossrefPubMedGoogle Scholar
  • 51 Zitvogel L, Mayordomo J I, Tjandrawan T, DeLeo A B, Clarke M R, Lotze M T, Storkus W J. Therapy of murine tumors with tumor peptide-pulsed dendritic cells: dependence on T cells, B7 costimulation, and T helper cell 1-associated cytokines.  J Exp Med. 1996;  183 (1) 87-97
    CrossrefPubMedGoogle Scholar

Dr. med. Ladislav Prikler

Klinik für Urologie · Kantonsspital

CH-9007 St. Gallen

Email: ladislav.prikler@kssg.ch

      >