A plant-derived Virus Like Particle versatile platform for specific antigen-delivery to dendritic cells: towards the development of an innovative anti-tumor vaccine
GUINGAND A. 1, TROLET A. 2, DANIEL D. 3, WAGNER R. 3, FLACHER V. 1, RITZENTHALER C. 2, POIGNAVENT V. 2, DUMORTIER H. 1
1 CNRS - UPR3572 - Immunologie Immunopathologie et Chimie Thérapeutique - Institut de Biologie Moléculaire et Cellulaire, Strasbourg, France; 2 CNRS - UPR2357 - Institut de Biologie Moléculaire des Plantes, Strasbourg, France; 3 CNRS - UMR7242 - Biotechnologie et Signalisation Cellulaire, Plateforme IMPReSs, Strasbourg, France
The paradigm in cancer treatment has shifted over the last decades: while conventional anti-tumoral therapies kill cancer cells, emerging therapies harness key actors of the immune system to promote tumor-specific immune responses. For instance, some therapeutic agents augment dendritic cell (DC) tumor antigen presentation to enhance the priming of tumor-specific cytotoxic T lymphocytes. To that purpose, nanoparticles of various formulations are engineered: they encapsulate an antigen and display a dendritic cell-targeting moiety on their surface, therefore allowing both antigen protection and enhanced dendritic cell-specific delivery.
Objectives: Here we developed and characterized a new Virus-Like Particle versatile platform and validated its interest in cancer therapy.
Methods: Non-infectious self-assembling antigen-containing nanoparticles were produced in planta from the capsid protein of the Grapevine Fanleaf Virus (VLPGFLV) (Belval et al., 2016), their surface was functionalized via nanobodies coupled to antibodies targeting DC. In our study, the ovalbumin model antigen was chosen and addressed to Clec9A, a C-type lectin selectively expressed by type 1 conventional DC (the DC subset specialized in antigen cross-presentation) (Caminschi et al., 2008). We evaluated in vitro and in vivo the ability of Clec9A-targeted VLPGFLV to promote antigen delivery and assessed the subsequent transgenic OVA-specific CD4 and CD8 T lymphocyte activation as well as the endogenic OVA-specific CD8 T lymphocyte activation.
Results: We demonstrate that targeting OVA-containing VLPGFLV to Clec9A efficiently promotes T lymphocyte activation resulting, in vivo, in a specific, systemic and efficient cytotoxic T lymphocyte response. Notably, we found that VLPGFLV are devoid of self-adjuvanting properties: the co-administration of a DC maturation agent (poly I:C) is therefore required. Finally, we are currently evaluating whether Clec9A-targeted OVA-containing VLPGFLV provide prophylactic and/or therapeutic protection against OVA-expressing B16 melanoma.
Conclusion: VLPGFLV is a promising platform for anti-tumoral applications as it efficiently promotes a cytotoxic immune response specific for the contained antigen.