Research projects

One of the current major challenges in cancer immunotherapy is ensuring that the immune system may recognize the tumor as a potential foreign agent. Tumor foreignness is nowadays considered as a potential marker of response to immune-checkpoint blockade immunotherapy. Tumor foreignness is determined by the rate mutations accumulated in the tumor (mutanoma). Some of these potential tumor antigens might be hidden from the immune system by a mechanism known as nonsense-mediated mRNA decay (NMD). In this project, we aim to inhibit NMD activity in the tumor by using an aptamer-siRNA based therapeutic platform that allows us to target a siRNA specific for a key NMD factor to the tumor cells. So far, we have already generated a best-in-class aptamer NMD-siRNA chimera that inhibits NMD activity in several tumor models tested in vitro and in vivo. In parallel, we engineered different tumor cell lines to inhibit NMD by using CRISPR/Cas9 technology. The antitumor effect of NMD was similar in the CRISPR/Cas9 NMD KO cell lines to those treated with the aptamer-siRNA chimera.

In all the in vivo tumor mouse models, we have observed a significant reduction in the tumor growth, which leads to higher infiltration of CD8 lymphocytes. CD8 lymphocytes are key players in the recognition and elimination of tumor cells. However, they still display an exhausted phenotype highlighting the need to reinvigorate the cells. The tumor microenvironment becomes quite immunosuppressive by the recruitment of T-regulatory lymphocytes and by the expression of co-inhibitor receptors. In this line of research, we are developing immunomodulatory aptamers that can potentiate lymphocyte expansion, thereby counteracting the immunosuppressive signal in the tumor milieu. The therapeutic intervention with this immunostimulatory aptamers might improve the response rate of the existing immunotherapy approaches already used in oncologic patients.