Abstract
Central tolerance to self-antigens is formed in the thymus where deletion of clones with high affinity to “self” takes place. Expression of peripheral antigens in the thymus has been implicated in T cell tolerance and autoimmunity. During the last years, it has been shown that medullary thymic epithelial cells (mTECs) are the unique cell type expressing a diverse range of tissue-specific antigens. Promiscuous gene expression is a cell autonomous property of thymic epithelial cells and is maintained during the entire period of thymic T cell output. The array of promiscuously expressed self-antigens was random and included well-known targets for cancer immunotherapy, such as α -fetoprotein, P1A, tyrosinase, and gp100. Gene expression in normal tissues may result in tolerance of high-avidity cytotoxic T lymphocyte (CTL), leaving behind low-avidity CTL that cannot provide effective immunity against tumors expressing the relevant target antigens. Thus, it may be evident that tumor vaccines that targeted the tumor-associated antigens should be inefficient due to the loss of high-avidity T cell clones capable to be stimulated. Stauss with colleagues have described a strategy to circumvent immunological tolerance that can be used to generate high-avidity CTL against self-proteins, including human tumor-associated antigens. In this strategy, the allorestricted repertoire of T cells from allogenic donor is used as a source of T cell clones with high avidity to tumor antigens of recipient for adoptive immunotherapy. Then, the T cell receptor (TCR) genes isolated from antigen-specific T cells can be exploited as generic therapeutic molecules for antigen-specific immunotherapy.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Amrolia, P.J., Reid, S.D., Gao, L., Schultheis, B., Dotti, G., Brenner, M.K., Melo, J.V., Goldman, J.M. and Stauss, H.J. (2003) Allorestricted cytotoxic T cells specific for human CD45 show potent antileukemic activity. Blood 101, 1007–1014.
Anderson, M.S., Venanzi, E.S., Chen, Z., Berzins, S.P., Benoist, C. and Mathis, D. (2005) The cellular mechanism of Aire control of T cell tolerance. Immunity 23, 227–239.
Brandle, D., Brasseur, F., Weynants, P., Boon, T. and Van den Eynde, B. (1996) A mutated HLA-A2 molecule recognized by autologous cytotoxic T lymphocytes on a human renal cell carcinoma. J. Exp. Med. 183, 2501–2508.
Cerundolo, V., Elliott, T., Elvin, J., Bastin, J., Rammensee, H.G. and Townsend, A. (1991) The binding affinity and dissociation rates of peptides for class I major histocompatibility complex molecules. Eur. J. Immunol. 21, 2069–2075.
Cohen, C.J., Zhao, Y., Zheng, Z., Rosenberg, S.A. and Morgan, R.A. (2006) Enhanced antitumor activity of murine-human hybrid T cell receptor (TCR) in human lymphocytes is associated with improved pairing and TCR/CD3 stability. Cancer Res. 66, 8878–8886.
Coulie, P.G., Lehmann, F., Lethe, B., Herman, J., Lurquin, C., Andrawiss, M. and Boon, T. (1995) A mutated intron sequence codes for an antigenic peptide recognized by cytolytic T lymphocytes on a human melanoma. Proc. Natl. Acad. Sci. U.S.A. 92, 7976–7980.
Dubey, P., Hendrickson, R.C., Meredith, S.C., Siegel, C.T., Shabanowitz, J., Skipper, J.C., Engelhard, V.H., Hunt, D.F. and Schreiber, H. (1997) The immunodominant antigen of an ultraviolet-induced regressor tumor is generated by a somatic point mutation in the DEAD box helicase p68. J. Exp. Med. 185, 695–705.
Egger, G., Liang, G., Aparicio, A. and Jones, P.A. (2004) Epigenetics in human disease and prospects for epigenetic therapy. Nature 429, 457–463.
Falk, K., Rotzschke, O. Stevanovic, S., Jung, G. and Rammensee, H.G. (1991a) Allele-specific motifs revealed by sequencing of self-peptides eluted from MHC molecules. Nature 351, 290–296.
Falk, K., Rotzschke, O., Deres, K., Metzger, J., Jung, G. and Rammensee, H.G. (1991b) Identification of naturally processed viral nonapeptides allows their quantification in infected cells and suggests an allele-specific T cell epitope forecast. J. Exp. Med. 174, 425–434.
Falk, K., Rotzschke, O. and Rammensee, H.G. (1990) Cellular peptide composition governed by major histocompatibility complex class I molecules. Nature 348, 248–251.
Felsher, D.W. (2003) Cancer revoked: oncogenes as therapeutic targets. Nat. Rev. Cancer 3, 375–380.
Gao, L., Bellantuono, I., Elsasser, A., Marley, S.B., Gordon, M.Y., Goldman, J.M. and Stauss, H.J. (2000) Selective elimination of leukemic CD34+progenitor cells by cytotoxic T lymphocytes specific for WT1. Blood 95, 2198–2203.
Golovkina, T.V., Chervonsky, A., Dudley, J.P. and Ross, S.R. (1992) Transgenic mouse mammary tumor virus superantigen expression prevents viral infection. Cell 69, 637–645.
Hahn, W.C. and Weinberg, R.A. (2002) Rules for making human tumor cells. N. Engl. J. Med. 347, 1593–1603.
Kalbus, M., Fleckenstein, B.T., Offenhausser, M., Bluggel, M., Melms, A., Meyer, H.E., Rammensee, H.G., Martin, R., Jung, G. and Sommer, N. (2001) Ligand motif of the autoimmune disease-associated mouse MHC class II molecule H2-As. Eur. J. Immunol. 31, 551–562.
Li, E. (2002) Chromatin modification and epigenetic reprogramming in mammalian development. Nat. Rev. Genet. 3, 662–673.
Logunova, N.N., Viret, C., Pobezinsky, L.A., Miller, S.A., Kazansky, D.B., Sundberg, J.P. and Chervonsky, A.V. (2005) Restricted MHC-peptide repertoire predisposes to autoimmunity. J. Exp. Med. 202, 73–84.
Monach, P.A., Meredith, S.C., Siegel, C.T. and Schreiber, H. (1995) A unique tumor antigen produced by a single amino acid substitution. Immunity 2, 45–59.
Morris, E.C., Tsallios, A., Bendle, G.M., Xue, S.A. and Stauss, H.J. (2005) A critical role of T cell antigen receptor-transduced MHC class I-restricted helper T cells in tumor protection. Proc. Natl. Acad. Sci. U.S.A. 102, 7934–7939.
Munz, C., Hofmann, M., Yoshida, K., Moustakas, A.K., Kikutani, H., Stevanovic, S., Papadopoulos, G.K. and Rammensee, H.G. (2002) Peptide analysis, stability studies, and structural modeling explain contradictory peptide motifs and unique properties of the NOD mouse MHC class II molecule H2-Ag7. Eur. J. Immunol. 32, 2105–2116.
Pelleitier, M. and Montplaisir, S. (1975) The nude mouse: a model of deficient T cell function. Methods Achiev. Exp. Pathol. 7, 149–166.
Pobezinskaya, Y., Chervonsky, A.V. and Golovkina, T.V. (2004) Initial stages of mammary tumor virus infection are superantigen independent. J. Immunol. 172, 5582–5587.
Prehn, R.T. (2005) On the nature of cancer and why anticancer vaccines don’t work. Cancer Cell Int. 5, 25.
Prehn, R.T. and Main, J.M. (1957) Immunity to methylcholanthrene-induced sarcomas. J. Natl. Cancer Inst. 18, 769–778.
Rammensee, H.G. (1995) Chemistry of peptides associated with MHC class I and class II molecules. Curr. Opin. Immunol. 7, 85–96.
Rammensee, H.G., Falk, K. and Rotzschke, O. (1993) Peptides naturally presented by MHC class I molecules. Annu. Rev. Immunol. 11, 213–244.
Reche, P.A., Glutting, J.P., Zhang, H. and Reinherz, E.L. (2004) Enhancement to the RANKPEP resource for the prediction of peptide binding to MHC molecules using profiles. Immunogenetics 56, 405–419.
Robbins, P.F., El-Gamil, M., Li, Y.F., Kawakami, Y., Loftus, D., Appella, E. and Rosenberg, S.A. (1996) A mutated beta-catenin gene encodes a melanoma-specific antigen recognized by tumor infiltrating lymphocytes. J. Exp. Med. 183, 1185–1192.
Rosenberg, S.A., Sherry, R.M., Morton, K.E., Scharfman, W.J., Yang, J.C., Topalian, S.L., Royal, R.E., Kammula, U., Restifo, N.P., Hughes, M.S., Schwartzentruber, D., Berman, D.M., Schwarz, S.L., Ngo, L.T., Mavroukakis, S.A., White, D.E. and Steinberg, S.M. (2005) Tumor progression can occur despite the induction of very high levels of self/tumor antigen-specific CD8+ T cells in patients with melanoma. J. Immunol. 175, 6169–6176.
Rotzschke, O., Falk, K., Deres, K., Schild, H., Norda, M., Metzger, J., Jung, G. and Rammensee, H.G. (1990) Isolation and analysis of naturally processed viral peptides as recognized by cytotoxic T cells. Nature 348, 252–254.
Rotzschke, O., Falk, K., Stevanovic, S., Jung, G., Walden, P. and Rammensee, H.G. (1991) Exact prediction of a natural T cell epitope. Eur. J. Immunol. 21, 2891–2894.
Sadovnikova, E., Jopling, L.A., Soo, K.S. and Stauss, H.J. (1998) Generation of human tumor-reactive cytotoxic T cells against peptides presented by non-self HLA class I molecules. Eur. J. Immunol. 28, 193–200.
Sadovnikova, E. and Stauss, H.J. (1996) Peptide-specific cytotoxic T lymphocytes restricted by nonself major histocompatibility complex class I molecules: reagents for tumor immunotherapy. Proc. Natl. Acad. Sci. U.S.A. 93, 13114–13118.
Sadovnikova, E., Parovichnikova, E.N., Savchenko, V.G., Zabotina, T. and Stauss, H.J. (2002) The CD68 protein as a potential target for leukaemia-reactive CTL. Leukemia 16, 2019–2026.
Sharkey, F.E. and Fogh, J. (1979) Incidence and pathological features of spontaneous tumors in athymic nude mice. Cancer Res. 39, 833–839.
Sherman, L.A., Theobald, M., Morgan, D., Hernandez, J., Bacik, I., Yewdell, J., Bennink, J. and Biggs, J. (1998) Strategies for tumor elimination by cytotoxic T lymphocytes. Crit. Rev. Immunol. 18, 47–54.
Simpson, A.J., Caballero, O.L., Jungbluth, A., Chen, Y.T. and Old, L.J. (2005) Cancer/testis antigens, gametogenesis and cancer. Nat. Rev. Cancer 5, 615–625.
Sommermeyer, D., Neudorfer, J., Weinhold, M., Leisegang, M., Engels, B., Noessner, E., Heemskerk, M.H., Charo, J., Schendel, D.J., Blankenstein, T., Bernhard, H. and Uckert, W. (2006) Designer T cells by T cell receptor replacement. Eur. J. Immunol. 36, 3052–3059.
Su, M.A. and Anderson, M.S. (2004) Aire: an update. Curr. Opin. Immunol. 16, 746–752.
Svane, I.M., Boesen, M. and Engel, A.M. (1999) The role of cytotoxic T lymphocytes in the prevention and immune surveillance of tumors - lessons from normal and immunodeficient mice. Med. Oncol. 16, 223–238.
Svane, I.M., Engel, A.M., Nielsen, M.B., Ljunggren, H.G., Rygaard, J. and Werdelin, O. (1996) Chemically induced sarcomas from nude mice are more immunogenic than similar sarcomas from congenic normal mice. Eur. J. Immunol. 26, 1844–1850.
Van Der Bruggen, P., Zhang, Y., Chaux, P., Stroobant, V., Panichelli, C., Schultz, E.S., Chapiro, J., Van Den Eynde, B.J., Brasseur, F. and Boon, T. (2002) Tumor-specific shared antigenic peptides recognized by human T cells. Immunol. Rev. 188, 51–64.
Vartdal, F., Johansen, B.H., Friede, T., Thorpe, C.J., Stevanovic, S., Eriksen, J.E., Sletten, K., Thorsby, E., Rammensee, H.G. and Sollid, L.M. (1996) The peptide binding motif of the disease associated HLA-DQ (alpha 1* 0501, beta 1* 0201) molecule. Eur. J. Immunol. 26, 2764–2772.
Wallny, H.J., Deres, K., Faath, S., Jung, G., Van Pel, A., Boon, T. and Rammensee, H.G. (1992b) Identification and quantification of a naturally presented peptide as recognized by cytotoxic T lymphocytes specific for an immunogenic tumor variant. Int. Immunol. 4, 1085–1090.
Wallny, H.J., Rotzschke, O., Falk, K., Hammerling, G. and Rammensee, H.G. (1992a) Gene transfer experiments imply instructive role of major histocompatibility complex class I molecules in cellular peptide processing. Eur. J. Immunol. 22, 655–659.
Ward, P.L., Koeppen, H.K., Hurteau, T., Rowley, D.A. and Schreiber, H. (1990) Major histocompatibility complex class I and unique antigen expression by murine tumors that escaped from CD8+T cell-dependent surveillance. Cancer Res. 50, 3851–3858.
Willemsen, R.A., Debets, R., Chames, P. and Bolhuis, R.L. (2003) Genetic engineering of T cell specificity for immunotherapy of cancer. Hum. Immunol. 64, 56–68.
Wilson, D.B., Wilson, D.H., Schroder, K., Pinilla, C., Blondelle, S., Houghten, R.A. and Garcia, K.C. (2004) Specificity and degeneracy of T cells. Mol. Immunol. 40, 1047–1055.
Wolfel, T., Hauer, M., Schneider, J., Serrano, M., Wolfel, C., Klehmann-Hieb, E., De Plaen, E., Hankeln, T., Meyer zum Buschenfelde, K.H. and Beach, D. (1995) A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma. Science 269, 1281–1284.
Woodruff, M.F. and Hodson, B.A. (1985) The effect of passage in vitro and in vivo on the properties of murine fibrosarcomas I. Tumorigenicity and immunogenicity. Br. J. Cancer 51, 161–169.
Xu, X.N. and Screaton, G.R. (2002) MHC/peptide tetramer-based studies of T cell function. J. Immunol. Methods 268, 21–28.
Xue, S., Gillmore, R., Downs, A., Tsallios, A., Holler, A., Gao, L., Wong, V., Morris, E. and Stauss, H.J. (2005) Exploiting T cell receptor genes for cancer immunotherapy. Clin. Exp. Immunol. 139, 167–172.
Zerrahn, J., Held, W. and Raulet, D.H. (1997) The MHC reactivity of the T cell repertoire prior to positive and negative selection. Cell 88, 627–636.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2007 Springer Science+Business Media, LLC
About this paper
Cite this paper
Kazansky, D.B. (2007). Intrathymic Selection: New Insight into Tumor Immunology. In: Shurin, M.R., Smolkin, Y.S. (eds) Immune-Mediated Diseases. Advances in Experimental Medicine and Biology, vol 601. Springer, New York, NY. https://doi.org/10.1007/978-0-387-72005-0_14
Download citation
DOI: https://doi.org/10.1007/978-0-387-72005-0_14
Publisher Name: Springer, New York, NY
Print ISBN: 978-0-387-72004-3
Online ISBN: 978-0-387-72005-0
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)