The Journal of Immunology, Vol 156, Issue 10 3911-3918, Copyright © 1996 by American Association of Immunologists

ARTICLES

Enhanced tumor outgrowth after peptide vaccination. Functional deletion of tumor-specific CTL induced by peptide vaccination can lead to the inability to reject tumors

RE Toes, RJ Blom, R Offringa, WM Kast and CJ Melief
Department of Immunohematology and Blood Bank, University Hospital, Leiden, The Netherlands.

CTL can play an important role in the defense against tumors. Protective CTL-mediated immunity can be established in animal tumor models after vaccination with synthetic peptides representing CTL epitopes. We now report that immunization with synthetic peptides can also lead to CTL tolerance associated with the inability to reject tumors. B6 tumor cells transformed by the human adenovirus early region 1 (Ad5E1) present an Ad5E1A- and an Ad5E1B-encoded CTL epitope to the immune system. CTL clones directed against either of these epitopes are able to eradicate established Ad5E1-induced tumors, showing that these CTL epitopes are targets of CTL that can mediate tumor regression. Here, we show that protective immunity against Ad5E1-expressing tumor cells can be established by immunization with Ad5E1-transformed cells and with an adenovirus vector containing the Ad5E1 region. Protective immunity, in either case, is associated with specific CTL memory. To test whether vaccination with synthetic peptides leads to protection against Ad5E1-expressing tumor cells, we vaccinated mice s.c. with a low dose of the Ad5E1B peptide. This peptide was chosen because the CTL response against the Ad5E1B-encoded CTL epitope contributes most to the antitumor response in B6 mice after vaccination with Ad5E1-transformed cells. Ad5E1B peptide-vaccinated mice were not protected against the outgrowth of Ad5E1-expressing tumor cells, but instead were no longer able to reject a tumor inoculum that was rejected by nonvaccinated mice. Moreover, the protection induced by tumor cell vaccination against Ad5E1B-expressing tumors was gone when the Ad5E1B-encoded CTL epitope was injected a few days before tumor challenge. This is associated with peptide-induced tolerance of Ad5E1B-specific CTL activity. These findings are relevant for the design of therapeutic approaches against both malignancies and T cell-mediated autoimmune diseases.

This article has been cited by other articles:

				M. S. Bijker, S. J. F. van den Eeden, K. L. Franken, C. J. M. Melief, R. Offringa, and S. H. van der Burg CD8+ CTL Priming by Exact Peptide Epitopes in Incomplete Freund's Adjuvant Induces a Vanishing CTL Response, whereas Long Peptides Induce Sustained CTL Reactivity J. Immunol., October 15, 2007; 179(8): 5033 - 5040. [Abstract] [Full Text] [PDF]

				M. Kim, H.-B. Moon, K. Kim, and K.-Y. Lee Antigen dose governs the shaping of CTL repertoires in vitro and in vivo Int. Immunol., March 1, 2006; 18(3): 435 - 444. [Abstract] [Full Text] [PDF]

				A. J. Johnson, Y. Mendez-Fernandez, A. M. Moyer, C. R. Sloma, I. Pirko, M. S. Block, M. Rodriguez, and L. R. Pease Antigen-Specific CD8+ T Cells Mediate a Peptide-Induced Fatal Syndrome J. Immunol., June 1, 2005; 174(11): 6854 - 6862. [Abstract] [Full Text] [PDF]

				P. Krebs, E. Scandella, B. Odermatt, and B. Ludewig Rapid Functional Exhaustion and Deletion of CTL following Immunization with Recombinant Adenovirus J. Immunol., April 15, 2005; 174(8): 4559 - 4566. [Abstract] [Full Text] [PDF]

				R. A. Wilcox, K. Tamada, D. B. Flies, G. Zhu, A. I. Chapoval, B. R. Blazar, W. M. Kast, and L. Chen Ligation of CD137 receptor prevents and reverses established anergy of CD8+ cytolytic T lymphocytes in vivo Blood, January 1, 2004; 103(1): 177 - 184. [Abstract] [Full Text] [PDF]

				T. Storni, C. Ruedl, W. A. Renner, and M. F. Bachmann Innate Immunity Together with Duration of Antigen Persistence Regulate Effector T Cell Induction J. Immunol., July 15, 2003; 171(2): 795 - 801. [Abstract] [Full Text] [PDF]

				L. Krishnan, S. Sad, G. B. Patel, and G. D. Sprott Archaeosomes Induce Enhanced Cytotoxic T Lymphocyte Responses to Entrapped Soluble Protein in the Absence of Interleukin 12 and Protect against Tumor Challenge Cancer Res., May 15, 2003; 63(10): 2526 - 2534. [Abstract] [Full Text] [PDF]

				M. A. Steller Cervical Cancer Vaccines: Progress and Prospects Reproductive Sciences, September 1, 2002; 9(5): 254 - 264. [Abstract] [PDF]

				G. Parmiani, C. Castelli, P. Dalerba, R. Mortarini, L. Rivoltini, F. M. Marincola, and A. Anichini Cancer Immunotherapy With Peptide-Based Vaccines: What Have We Achieved? Where Are We Going? J Natl Cancer Inst, June 5, 2002; 94(11): 805 - 818. [Abstract] [Full Text] [PDF]

				D. Valmori, V. Dutoit, V. Schnuriger, A.-L. Quiquerez, M. J. Pittet, P. Guillaume, V. Rubio-Godoy, P. R. Walker, D. Rimoldi, D. Lienard, et al. Vaccination with a Melan-A Peptide Selects an Oligoclonal T Cell Population with Increased Functional Avidity and Tumor Reactivity J. Immunol., April 15, 2002; 168(8): 4231 - 4240. [Abstract] [Full Text] [PDF]

				S. G. Smith, P. M. Patel, J. Porte, P. J. Selby, and A. M. Jackson Human Dendritic Cells Genetically Engineered to Express a Melanoma Polyepitope DNA Vaccine Induce Multiple Cytotoxic T-Cell Responses Clin. Cancer Res., December 1, 2001; 7(12): 4253 - 4261. [Abstract] [Full Text] [PDF]

				J.-S. Blanchet, D. Valmori, I. Dufau, M. Ayyoub, C. Nguyen, P. Guillaume, B. Monsarrat, J.-C. Cerottini, P. Romero, and J. E. Gairin A New Generation of Melan-A/MART-1 Peptides That Fulfill Both Increased Immunogenicity and High Resistance to Biodegradation: Implication for Molecular Anti-Melanoma Immunotherapy J. Immunol., November 15, 2001; 167(10): 5852 - 5861. [Abstract] [Full Text] [PDF]

				M. H. Kershaw, C. Hsu, W. Mondesire, L. L. Parker, G. Wang, W. W. Overwijk, R. Lapointe, J. C. Yang, R.-F. Wang, N. P. Restifo, et al. Immunization against Endogenous Retroviral Tumor-associated Antigens Cancer Res., November 1, 2001; 61(21): 7920 - 7924. [Abstract] [Full Text] [PDF]

				A C Armstrong and R E Hawkins Vaccines in oncology: background and clinical potential Br. J. Radiol., November 1, 2001; 74(887): 991 - 1002. [Abstract] [Full Text] [PDF]

				S. Weijzen, S. C. Meredith, M. P. Velders, A. G. Elmishad, H. Schreiber, and W. M. Kast Pharmacokinetic Differences Between a T Cell-Tolerizing and a T Cell-Activating Peptide J. Immunol., June 15, 2001; 166(12): 7151 - 7157. [Abstract] [Full Text] [PDF]

				M. Toungouz, M. Libin, F. Bulte, L. Faid, F. Lehmann, D. Duriau, M. Laporte, D. Gangji, C. Bruyns, M. Lambermont, et al. Transient expansion of peptide-specific lymphocytes producing IFN-{gamma} after vaccination with dendritic cells pulsed with MAGE peptides in patients with mage-A1/A3-positive tumors J. Leukoc. Biol., June 1, 2001; 69(6): 937 - 943. [Abstract] [Full Text] [PDF]

				V. Monsurro, M.-B. Nielsen, A. Perez-Diez, M. E. Dudley, E. Wang, S. A. Rosenberg, and F. M. Marincola Kinetics of TCR Use in Response to Repeated Epitope-Specific Immunization J. Immunol., May 1, 2001; 166(9): 5817 - 5825. [Abstract] [Full Text] [PDF]

				I. Miconnet, I. Coste, F. Beermann, J.-F. Haeuw, J.-C. Cerottini, J.-Y. Bonnefoy, P. Romero, and T. Renno Cancer Vaccine Design: A Novel Bacterial Adjuvant for Peptide-Specific CTL Induction J. Immunol., April 1, 2001; 166(7): 4612 - 4619. [Abstract] [Full Text] [PDF]

				J. van Bergen, M. Camps, R. Offringa, C. J. M. Melief, F. Ossendorp, and F. Koning Superior Tumor Protection Induced by a Cellular Vaccine Carrying a Tumor-specific T Helper Epitope by Genetic Exchange of the Class II-associated Invariant Chain Peptide Cancer Res., November 1, 2000; 60(22): 6427 - 6433. [Abstract] [Full Text]

				N. Haicheur, E. Bismuth, S. Bosset, O. Adotevi, G. Warnier, V. Lacabanne, A. Regnault, C. Desaymard, S. Amigorena, P. Ricciardi-Castagnoli, et al. The B Subunit of Shiga Toxin Fused to a Tumor Antigen Elicits CTL and Targets Dendritic Cells to Allow MHC Class I-Restricted Presentation of Peptides Derived from Exogenous Antigens J. Immunol., September 15, 2000; 165(6): 3301 - 3308. [Abstract] [Full Text] [PDF]

				P. Mukherjee, A. R. Ginardi, C. S. Madsen, C. J. Sterner, M. C. Adriance, M. J. Tevethia, and S. J. Gendler Mice with Spontaneous Pancreatic Cancer Naturally Develop MUC-1-Specific CTLs That Eradicate Tumors When Adoptively Transferred J. Immunol., September 15, 2000; 165(6): 3451 - 3460. [Abstract] [Full Text] [PDF]

				M.-B. Nielsen, V. Monsurro, S. A. Migueles, E. Wang, A. Perez-Diez, K.-H. Lee, U. Kammula, S. A. Rosenberg, and F. M. Marincola Status of Activation of Circulating Vaccine-Elicited CD8+ T Cells J. Immunol., August 15, 2000; 165(4): 2287 - 2296. [Abstract] [Full Text] [PDF]

				K.-H. Lee, E. Wang, M.-B. Nielsen, J. Wunderlich, S. Migueles, M. Connors, S. M. Steinberg, S. A. Rosenberg, and F. M. Marincola Increased Vaccine-Specific T Cell Frequency After Peptide-Based Vaccination Correlates with Increased Susceptibility to In Vitro Stimulation But Does Not Lead to Tumor Regression J. Immunol., December 1, 1999; 163(11): 6292 - 6300. [Abstract] [Full Text] [PDF]

				L. R. H. M. Schurmans, A. Th. den Boer, L. Diehl, E. I. H. van der Voort, W. M. Kast, C. J. M. Melief, R. E. M. Toes, and M. J. Jager Successful Immunotherapy of an Intraocular Tumor in Mice Cancer Res., October 1, 1999; 59(20): 5250 - 5254. [Abstract] [Full Text] [PDF]

				T.R.J. Evans and S.B. Kaye Vaccine therapy for cancer—fact or fiction? QJM, June 1, 1999; 92(6): 299 - 307. [Full Text] [PDF]

				N. Maitre, J. M. Brown, M. Demcheva, J. R. Kelley, M. A. Lockett, J. Vournakis, and D. J. Cole Primary T-Cell and Activated Macrophage Response Associated with Tumor Protection Using Peptide/Poly-N-Acetyl Glucosamine Vaccination Clin. Cancer Res., May 1, 1999; 5(5): 1173 - 1182. [Abstract] [Full Text] [PDF]

				Y. Men, I. Miconnet, D. Valmori, D. Rimoldi, J.-C. Cerottini, and P. Romero Assessment of Immunogenicity of Human Melan-A Peptide Analogues in HLA-A*0201/Kb Transgenic Mice J. Immunol., March 15, 1999; 162(6): 3566 - 3573. [Abstract] [Full Text] [PDF]

				T. F. Greten and E. M. Jaffee Cancer Vaccines J. Clin. Oncol., March 1, 1999; 17(3): 1047 - 1047. [Abstract] [Full Text] [PDF]

				H. J. Zeh III, D. Perry-Lalley, M. E. Dudley, S. A. Rosenberg, and J. C. Yang High Avidity CTLs for Two Self-Antigens Demonstrate Superior In Vitro and In Vivo Antitumor Efficacy J. Immunol., January 15, 1999; 162(2): 989 - 994. [Abstract] [Full Text] [PDF]

				R. C. Fields, K. Shimizu, and J. J. Mule Murine dendritic cells pulsed with whole tumor lysates mediate potent antitumor immune responses in vitro and in vivo PNAS, August 4, 1998; 95(16): 9482 - 9487. [Abstract] [Full Text] [PDF]

				R. E. M. Toes, E. I. H. van der Voort, S. P. Schoenberger, J. W. Drijfhout, L. van Bloois, G. Storm, W. M. Kast, R. Offringa, and C. J. M. Melief Enhancement of Tumor Outgrowth Through CTL Tolerization After Peptide Vaccination Is Avoided by Peptide Presentation on Dendritic Cells J. Immunol., May 1, 1998; 160(9): 4449 - 4456. [Abstract] [Full Text] [PDF]

				Y. Ohtsuka, K. Udaka, Y. Yamashiro, H. Yagita, and K. Okumura Dystrophin Acts as a Transplantation Rejection Antigen in Dystrophin-Deficient Mice: Implication for Gene Therapy J. Immunol., May 1, 1998; 160(9): 4635 - 4640. [Abstract] [Full Text] [PDF]

				A.-M. T. Ciupitu, M. Petersson, C. L. O'Donnell, K. Williams, S. Jindal, R. Kiessling, and R. M. Welsh Immunization with a Lymphocytic Choriomeningitis Virus Peptide Mixed with Heat Shock Protein 70 Results in Protective Antiviral Immunity and Specific Cytotoxic T Lymphocytes J. Exp. Med., March 2, 1998; 187(5): 685 - 691. [Abstract] [Full Text] [PDF]

				F. Ossendorp, E. Mengede, M. Camps, R. Filius, and C. J.M. Melief Specific T Helper Cell Requirement for Optimal Induction of Cytotoxic T Lymphocytes against Major Histocompatibility Complex Class II Negative Tumors J. Exp. Med., March 2, 1998; 187(5): 693 - 702. [Abstract] [Full Text] [PDF]

				H. L. Greenstone, J. D. Nieland, K. E. de Visser, M. L. H. De Bruijn, R. Kirnbauer, R. B. S. Roden, D. R. Lowy, W. M. Kast, and J. T. Schiller Chimeric papillomavirus virus-like particles elicit antitumor immunity against the E7 oncoprotein in an HPV16 tumor model PNAS, February 17, 1998; 95(4): 1800 - 1805. [Abstract] [Full Text] [PDF]

				R. E. M. Toes, R. C. Hoeben, E. I. H. van der Voort, M. E. Ressing, A. J. van der Eb, C. J. M. Melief, and R. Offringa Protective anti-tumor immunity induced by vaccination with recombinant adenoviruses encoding multiple tumor-associated cytotoxic T lymphocyte epitopes in a string-of-beads fashion PNAS, December 23, 1997; 94(26): 14660 - 14665. [Abstract] [Full Text] [PDF]