PIMOZIDE: A NOVEL/OLD DRUG THAT ENHANCES CROSS PRESENTATION OF ANTIGENS MEDIATING THE AUGMENT OF ANTIGEN TRANSLOCATION TO THE CYTOSOL IN DENDRITIC CELLS

Congreso; LXXI REUNIÓN SAI; 2023

Dendritic cells (DCs) are professional Antigen Presenting Cells (APCs) responsiblefor activating naive T lymphocytes to induce specific response against antigens. Inparticular, DCs have the special ability to internalize exogenous antigens and crosspresent (XP) them in MHCI context to induce cytotoxic CD8+ T cell (CTL) response,which can be potentially exploited for immunotherapeutic purposes. Our group isinterested in searching for new adjuvants able to improve CTL response. In thatcontext, we performed a high throughput screening (HTS) to identify newcompounds that could potentiate XP, using an assay developed in our laboratorybased on JAWSII DCs line and soluble OVA as antigen (sOVA). In this work, weanalyzed the mechanisms underlying XP potentiation of Pimozide (P), one of the 5hits identified after HTS. We observed that P does not modify sOVA internalization,and neither MHC I-surface expression in DCs. It has been reported that Paccumulates in acidic compartments and acts as a lysosomotropic drug. Thus westudied if P accumulates in lysosomes. After blocking endo phagosomal acidification,P effect on DCs XP was diminished. We also observed that incubation of DCs with Pincreased antigen translocation from endosomes to the cytosol, a key step in XP.Taking all these results into account, our evidence suggests that P affects endophagosomal processing of antigens on DCs. Further studies will be engaged tocompletely understand the mechanisms involved in enhancing XP.