INCEPTOR · Investigate the mode of action ofInvestigate the mode of action of beta-carboline derivative Harmine on increasing MHC-I expression and potentiating the Immune Checkpoint Blockade cancer immunotherapy

One of the major mechanisms by which solid tumors escape anti-tumor immunity is the downregulation of major histocompatibility complex class I (MHC-I), which causes a failure in the recognition of tumor cells by the cytotoxicity T-cells. The project proposed by Dr. Teresa Ramos contains basic and translational aspects. The basic aspect relies on investigating the mechanisms of action of the ACB1801 molecule (harmine), reported by the host team to restore the MHC-I in tumor cells, using state-of-the-art technologies. The translational aspect of the project relies on providing the preclinical proof of concept for an innovative immunotherapy combination. The combination strategy consists of using a vaccination approach with Dendritic Cells (DC), pulsed with tumor cells pre-treated with ACB1801, in combination with immune checkpoint blockades. Although DC vaccination constitutes potent anticancer immunotherapy, clinical data showed that it does not provide robust benefits to patients. the innovative strategy of the project is based on simultaneous boosting the DC-based vaccine by ACB1801 and unleashing the power of T cells to induce a robust anti-tumor immune response which constitutes an unmet clinical need. The development of the present proposal will enable Dr. Ramos to achieve a broad range of new technologies and management skills through a variety of multidisciplinary training programs. This will represent a key step toward her final objective to become an independent and competitive scientist.