Estudio de la implicación de la presentación cruzada de antígenos en la actividad antitumoral de anticuerpos monoclonales inmunoestimulantes

Abstract

This PhD project has served to uncover the essential role cDC1s and cross-presentation play in the success of the immunotherapeutic agents anti-PD-1 and anti-CD137, analogous to those available in the clinic and that have revolutionized treatment of cancer. We have done so in loss-of-function settings using mouse genetically deficient for Batf3 and devoid of cDC1s, which displayed complete unresponsiveness to immunotherapy. Next, we have devised gain-of-function experiments aimed to systemically and locally expand cDC1 populations, while at the same time providing local activation signals to mature them. In the first chapter, we chose to expand cDC1s by systemically administering sFlt3L through hydrodynamic injection of sFlt3L-coding plasmid, and to locally activate them by intratumoral injection of Hiltonol®, Poly-ICLC, a TLR3 agonist available in the clinic. In the second chapter, we cloned XCL1 and sFlt3L into a Semliki Forest Virus vector (SFV-XF) for intratumoral administration. In this setting, both transgenes were intended to cause chemoattraction and differentiation of cDC1s, while viral RNA would provide the activation signals to drive DC maturation and potentiate CD8 T-cell cross-priming. Although we did not manage to detect increased cDC1 infiltration into injected tumors, SFV-XF showed robust antitumor efficacy against different tumor models in mice and promoted accumulation of conventional DCs in tumor-draining and distant lymph nodes.