Invited lecture: Mechanisms of tumoral immune resistance

Van den Eynde, Benoît [UCL]

A major factor limiting the efficacy of cancer immunotherapy is the development of local mechanisms allowing tumors to escape or resist immune rejection. An important escape mechanism is the loss of expression of the tumor antigen(s) targeted by the immune response. This can result from a loss of the encoding gene, a loss of MHC presenting molecules or a modulation of the antigen-processing machinery. We have observed that human tumors contain novel proteasome subtypes that are intermediate between the standard proteasome and the immunoproteasome, and differ in their ability to process tumor antigens recognized by CD8 T lymphocytes. We recently described the ability of the proteasome to produce antigenic peptides by a peptide splicing reaction involving a transpeptidation step. We have now also compared the ability of the different proteasome subtypes to produce these spliced peptides. Immune resistance mechanisms often involve modulation of the tumoral microenvironment resulting in local immunosuppression. One such mechanism 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. Another 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. Studying an inducible mouse melanoma model, we observed a correlation between aggressive tumor progression and the occurrence of exacerbated systemic inflammation, involving disruption of secondary lymphoid organs, extramedullary hematopoiesis and accumulation of immature myeloid cells, which may contribute to tumoral immune resistance.