Invited lecture: Tumor antigens and preclinical models for cancer immunotherapy

Van den Eynde, Benoît [UCL]

Immunotherapy based on therapeutic vaccination of cancer patients is a promising new approach for cancer therapy. It is based on the definition of tumor antigens recognized by cytolytic T lymphocytes. These antigens correspond to peptides produced by the proteasome during the degradation of intracellular proteins. These peptides are presented at the cell surface by MHC class I molecules. New results will be presented describing a new mode of production of antigenic peptides by the proteasome, which involves the splicing of peptide fragments, either in the normal or the reverse order (Vigneron et al. 2004 ; Warren et al. 2006). Clinical trials of cancer vaccines indicate that this approach is not toxic and leads to significant clinical benefit in a minority of patients. However, it appears that an important factor limiting the efficacy of immunotherapy in non-responsive patients is the development of mechanisms allowing tumors to resist or escape immune rejection. It is therefore critical to identify such mechanisms and design therapeutic approaches able to overcome it. A powerful tumor resistance mechanism is based on the expression by tumor cells of Indoleamine 2,3-dioxygenase (IDO), an intracellular enzyme that catalyses rapid tryptophan degradation, resulting in a local tryptophan depletion that severely affects T lymphocyte proliferation and is thereby profoundly immunosuppressive. We showed that many human tumors express IDO in a constitutive manner. We confirmed that tumoral IDO was enzymatically active. Making use of a preclinical model system, we also showed that this constitutive expression of IDO endows tumor cells with the ability to resist immune rejection by preventing T cell attack in vivo. Importantly, this effect was partly reverted by systemic treatment of mice with 1-methyl-L-tryptophan, an inhibitor of IDO. These results suggest that the efficacy of therapeutic vaccination of cancer patients could be improved by concomitant administration of an IDO inhibitor (Uyttenhove et al. 2003). Lastly, a new mouse model of inducible melanoma expressing a defined tumor antigen will be presented. This model will allow to refine the approaches of immunotherapy by taking into account the long-term interplay between the immune system and the tumor developing slowly within normal tissues in the autochthonous host (Huijbers et al. 2006). Huijbers I, Krimpenfort P, Chomez P, van der Valk MA, Song J-Y, Inderberg-Suso E-M, Schmitt-Verhulst A-M, Berns A, Van den Eynde BJ. An inducible mouse model of melanoma expressing a defined tumor antigen. Cancer Res 2006 ; 66 : 3278-86. Uyttenhove C, Pilotte L, Théate 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. Nature Med 2003 ; 9 : 1269-74. Vigneron N, Stroobant V, Chapiro J, Ooms A, Degiovanni G, Morel S, van der Bruggen P, Boon T, Van den Eynde BJ. An antigenic peptide produced by peptide splicing in the proteasome. Science 2004 ; 304 : 587-90. Warren EH, Vigneron NM, Coulie PG, Gavin MA, Stroobant V, Chapiro J, Dalet A, Tykodi SS, Xuereb SM, Mito JK, Riddell SR, Van den Eynde BJ. A minor histocompatibility antigen produced in the proteasome splicing of non-contiguous peptide fragments in the reverse order. Science 2006 ; 313 : 1444-47.