Despite the major breakthrough of immune-checkpoint inhibitors, only a limited number of patients respond to this treatment. Patients with pancreatic cancer, for example, failed to respond to these therapies. Since the abundance of intra-tumoral CD8+ T cells predict a better prognosis, these patients may benefit from an enhanced anti-tumor immunity.
Priming of CD8+ T cells by dendritic cells (DC) is crucial for the generation of effective anti-tumor immune responses. Since generating DC ex vivo is a laborious process, research is shifting towards targeting tumor antigens to naturally occurring DCs in vivo. In this study, we developed a liposomal vaccine carrier that delivers tumor antigens to human CD169/Siglec-1+ antigen-presenting cells using gangliosides as endogenous CD169-targeting ligands.
We observed that ganglioside-liposomes specifically bound to CD169 and were internalized by in vitro generated monocyte-derived DCs (moDCs) and macrophages, and by ex vivo isolated splenic macrophages in a CD169-dependent manner. In blood, unsupervised high-dimensional reduction analysis revealed that ganglioside-liposomes specifically targeted CD14+ CD169+ monocytes and Axl+ CD169+ DCs, a recently discovered DC subset. Liposomal co-delivery of tumor antigen and toll-like receptor ligand to CD169+ moDCs and Axl+ DCs led to cytokine production and robust cross-presentation and activation of tumor antigen-specific CD8+ T cells. Finally, we showed that Axl+ DCs were present in patients with gastrointestinal malignancies, pancreatic ductal adenocarcinoma, hepatocellular carcinoma, colorectal liver metastasis, and melanoma, and that they efficiently captured ganglioside-liposomes.
Our findings demonstrate a novel nanovaccine platform targeting CD169+ DC that can drive anti-tumor CD8+ T cell responses.
Alsya J. Affandi1, Joanna Grabowska1, Katarzyna Olesek1, Miguel Lopez Venegas1, Arnaud Barbaria1, Ernesto Rodríguez1, Patrick P.G. Mulder1, Helen J. Pijffers1, Martino Ambrosini1, Hakan Kalay1, Tom O’Toole1, Eline S. Zwart1,2, Geert Kazemier2, Kamran Nazmi3, Floris J. Bikker3, Alfons J.M. van den Eertwegh4, Tanja D. de Gruijl4, Yvette van Kooyk1, Joke M.M. den Haan*1
1Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
2Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
3Department of Oral Biochemistry, Academic Centre for Dentistry Amsterdam (ACTA), Vrije Universiteit Amsterdam and University of Amsterdam, Amsterdam, The Netherlands.
4Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.