Inserm U1015 - Immunologie des tumeurs et Immunothérapies, Institut Gustave Roussy, Franconville
Contact IRCM : Pierre Martineau
“Some years ago, it has been suggested that the majority of peptides presented through the Major Histocompatibility Complex class I (MHC-I) pathway was derived from the degradation of so-called defective ribosomal products or DRiPs. More recently, we have shown that antigen presentation is equivalent whether the epitope is expressed within an intron or an exon. Indeed, the MHC-I presentation pathway is supported by the so called Pioneer Translation Products (PTPs) which are polypeptides produced by translation events distinct from the canonical cytoplasmic translation.
We have recently reported the important role of PTPs in triggering CD8+ T cell activation via cross-presentation. Since then, it became important for us to demonstrate how PTPs can be a source of neoantigens for the development of therapeutic cancer vaccines. We have demonstrated that vaccination of mice with non-conventional epitopes can induce specific T cell activation and tumor growth defect. We aim at developing a technology platform to identify human non-conventional MHC-I epitopes that are unique or shared between different types of human cancers and that can be targeted in the context of synthetic long peptide (SLP)-based cancer vaccines.
Furthermore, we have also demonstrated that PTPs can be generated before mRNA splicing. Our lab has focused on understanding how antigen presentation in cancer cells can be positively regulated by enhancing the expression of PTPs. In collaboration with Dr. Mouad Alami (CoSMIT, Université Paris Saclay) we have generated few derivatives of the biflavonoid splicing inhibitor isoginkgetin. We demonstrated in vitro and in vivo that this compound and its water-soluble and non-toxic derivative IP2 increase PTP-derived antigen presentation in cancer cells in vitro and impairs tumor growth in vivo. IP2 action is long-lasting and dependent on the CD8+ T cell response to tumor antigens. Finally, we observed that the antigen repertoire displayed on MHC-I molecules at the surface of cancer cells is modified upon treatment with IP2. Not only this newly discovered immunomodulatory agent alters the presentation of pre-existing epitopes but it induce the emergence of novel antigens derived from both coding and allegedly non-coding sequences that can be a source of a specific peptides-based cancer vaccine.
We aim at screening other splicing inhibitors which may enhance the ability of the immune system to selectively recognize and attack cancer cells.”