Invited lecture: Fighting tumoral immune resistance

Van den Eynde, Benoît [UCL] van der Bruggen, Pierre [UCL]

A number of cancer vaccine trials have now been completed, and regressions of metastatic melanomas were observed in 10-20% of the patients, in the absence of any toxicity. It appears that an important factor limiting the efficacy of immunotherapy is the development of local mechanisms allowing tumors to resist immune rejection. The challenge is to identify such mechanisms and design therapeutic approaches to inactivate them so as to boost the efficacy of cancer immunotherapy. Two such mechanisms will be described. The first is based on the expression by tumor cells of Indoleamine 2,3-dioxygenase (IDO), a tryptophan-degrading enzyme inducing a local tryptophan depletion that severely affects T lymphocyte proliferation. Our data in a preclinical model indicate that the efficacy of therapeutic vaccination of cancer patients could be improved by concomitant administration of an inhibitor of IDO. The second mechanism is based on the expression by tumor cells of galectin-3, which induces T cell anergy by trapping TCR molecules in a lattice preventing their association with CD8 molecules. Anergy can be reversed with sugars that bind galectin-3. This work was supported in part by grants from the European Community under the Sixth Programme (convention “Cancerimmunotherapy”), and by belgian grants financed by the Région Wallonne under the programme BIOWIN (Convention “CANTOL”), the Fonds National de la Recherche Scientifique, and the Fondation contre le Cancer.