Tumor immunology and antigen processing group
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Benoît VAN DEN
EYNDE, Member
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Building up on the molecular definition of tumor antigens recognized by T cells, our group mainly focuses on two aspects of tumor immunology, namely the processing of tumor antigens and the study of animal models to optimize cancer immunotherapy and evaluate tumor resistance mechanisms.
Tumor antigens recognized by Cytolytic T Lymphocytes (CTL) consist of peptides that are presented by MHC molecules at the cell surface and derive from intracellular proteins that are degraded by the proteasome. The intracellular pathway leading from the protein to the peptide/MHC complex is known as "antigen processing". Our group focuses on the proteasome and recently described a new mode of production of antigenic peptides by the proteasome, based on cutting and pasting peptide fragments to form a new spliced peptide. The first example was a peptide derived from human melanocyte protein gp100. This antigenic peptide is nine-amino acid long and is produced by the splicing of two fragments that were initially non-contiguous in the parental protein. The splicing is made by the proteasome, is tightly coupled to the proteolytic reaction, and appears to occur by transpeptidation involving an acyl-enzyme intermediate. We are currently working on a second example of spliced peptide, where the two fragments are rearranged before splicing.
We are also studying the processing differences between the standard proteasome, which is present in most cells, and the immunoproteasome which is found in dendritic cells and in cells exposed to interferon-gamma. Several tumor antigens were found to be processed differently by the two proteasome types, usually because of a preferential cleavage made by one or the other proteasome within the antigenic peptide itself.
Translation of knowledge on tumor antigens into efficient cancer immunotherapy requires additional studies on the various strategies that can be used. Some of these studies can be done in preclinical animal models. The study of such a model allowed us to uncover a powerful mechanism of tumor resistance, which is based on tryptophan catabolism by indoleamine-2,3 dioxygenase, an enzyme that we found to be frequently expressed in tumors. The resulting local tryptophan shortage appears to prevent the proliferation of lymphocytes at the tumor site. Inhibitors of indoleamine-2,3 dioxygenase can be used in vivo to counteract this tumor resistance mechanism.
The currently available murine models are limited by the fact they are based on transplantation of tumor cells grown in vitro into a healthy animal. This does not recapitulate the long-term host/tumor relationship that occurs in humans when a tumor slowly develops within a normal tissue. To circumvent this limitation and obtain more relevant information from such preclinical models, we have build a new mouse melanoma model where tumors expressing a given antigen can be induced, using a transgenic system based on Cre-lox recombination.
- Differential
processing of tumor antigens by the standard
proteasome and the immunoproteasome
Jacques Chapiro, Vincent Stroobant, Benoît Guillaume, Benoît Vanholle, Wenbin Ma, Grégory Parvizi - Antigenic
peptides produced by peptide splicing in the
proteasome
Nathalie Vigneron, Vincent Stroobant, Jacques Chapiro, Alexandre Dalet (in collaboration with Edus Warren, Fred Hutchinson Cancer Research Center, Seattle, USA) - Identification of
new antigens recognized by autologous CTL on human
melanoma
Wenbin Ma, Nathalie Vigneron (in collaboration with P. Coulie) - A novel tumor immune
escape mechanism based on tryptophan degradation by
indoleamine 2,3 dioxygenase
Catherine Uyttenhove, Luc Pilotte, Ivan Théate, Dominique Donckers, Nicolas Parmentier, Vincent Stroobant, Didier Colau - An inducible mouse
model of melanoma expressing a defined tumor
antigen
Ivo Huijbers (in collaboration with Paul Krimperfort (NKI, Amsterdam) and Anne-Marie Schmitt-Verhulst (CIML, Marseille))
Selected publications
- Warren E.H., Vigneron N., Gavin M.A., Coulie P.G., Stroobant V., Dalet A., Tykodi S.S., Xuereb S.M., Mito J.K., Riddell S.R., Van den Eynde B.J. An Antigen Produced by Splicing of Non-Contiguous Peptides in the Reverse Order. Science 2006; 313 : 1444-1447
- Chapiro J, Claverol S, Piette F, Ma W, Stroobant V, Guillaume B, Gairin JE, Morel S, Burlet-Schiltz O, Monsarrat B, Boon T, Van den Eynde BJ. Destructive cleavage of antigenic peptides either by the immunoproteasome or by the standard proteasome results in differential antigen presentation. J Immunol 2006;176:1053-1061.
- Huijbers IJ, Krimpenfort P, Chomez P, van der Valk MA, Song JY, Inderberg-Suso EM, Schmitt-Verhulst AM, Berns A, Van den Eynde BJ. An inducible mouse model of melanoma expressing a defined tumor antigen. Cancer Res 2006;66:3278-3286.
- Vigneron N, Stroobant V, Chapiro J, Ooms A, Degiovanni G, Morel S, van der Bruggen P, Boon T, Van den Eynde B. An antigenic peptide produced by peptide splicing in the proteasome. Science 2004;304:587-90.
- Ma W, Germeau C, Vigneron N, Maernoudt A-S, Morel S, Boon T, Coulie PG, Van den Eynde BJ. Two new tumor-specific antigenic peptides encoded by gene MAGE-C2 and presented to cytolytic T lymphocytes by HLA-A2. Int J Cancer 2004;109:698-702.
- Uyttenhove C, Pilotte L, Theate I, Stroobant V, Colau D, Parmentier N, Boon T, Van den Eynde BJ. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med 2003;9:1269-74.
- Schultz ES, Chapiro J, Lurquin C, Claverol S, Burlet-Schiltz O, Warnier G, Russo V, Morel S, Levy F, Boon T, Van den Eynde BJ, van der Bruggen P. The production of a new MAGE-3 peptide presented to cytolytic T lymphocytes by HLA-B40 requires the immunoproteasome. J Exp Med 2002;195:391-9.
- Van den Eynde BJ, Morel S. Differential processing of class-I-restricted epitopes by the standard proteasome and the immunoproteasome. Curr Opin Immunol 2001;13:147-53.
- Probst-Kepper M, Stroobant V, Kridel R, Gaugler B, Landry C, Brasseur F, Cosyns JP, Weynand B, Boon T, Van Den Eynde BJ. An alternative open reading frame of the human macrophage colony-stimulating factor gene is independently translated and codes for an antigenic peptide of 14 amino acids recognized by tumor-infiltrating CD8 T lymphocytes. J Exp Med 2001;193:1189-98.
- Morel S, Levy F, Burlet-Schiltz O, Brasseur F, Probst-Kepper M, Peitrequin AL, Monsarrat B, Van Velthoven R, Cerottini JC, Boon T, Gairin JE, Van den Eynde BJ. Processing of some antigens by the standard proteasome but not by the immunoproteasome results in poor presentation by dendritic cells. Immunity 2000;12:107-17.
- Van Den Eynde BJ, Gaugler B, Probst-Kepper M, Michaux L, Devuyst O, Lorge F, Weynants P, Boon T. A new antigen recognized by cytolytic T lymphocytes on a human kidney tumor results from reverse strand transcription. J Exp Med 1999;190:1793-800.