Sensitization of glioblastoma tumor micro-environment to chemo- and immunotherapy by Galectin-1 intranasal knock-down strategy

• Published in: Scientific reports Vol. 7; no. 1; pp. 1217 - 14
• Main Authors: Van Woensel, Matthias, Mathivet, Thomas, Wauthoz, Nathalie, Rosière, Rémi, Garg, Abhishek D, Agostinis, Patrizia, Mathieu, Véronique, Kiss, Robert, Lefranc, Florence, Boon, Louis, Belmans, Jochen, Van Gool, Stefaan W, Gerhardt, Holger, Amighi, Karim, De Vleeschouwer, Steven
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 27.04.2017; Nature Publishing Group UK; Nature Portfolio
• Subjects: Administration, Intranasal; Animals; Brain cancer; CD4 antigen; CD8 antigen; Chemotherapy; Chitosan; Dendritic cells; Disease Models, Animal; Drug Therapy - methods; Galectin 1 - genetics; Galectin-1; Gene Knockdown Techniques; Glioblastoma; Glioblastoma - therapy; Immune checkpoint; Immunoregulation; Immunotherapy; Immunotherapy - methods; Inflammation; Lymphocytes T; Macrophages; Mice; Nanoparticles; Nose; PD-1 protein; RNA, Small Interfering - administration & dosage; siRNA; Suppressor cells; Temozolomide; Treatment Outcome; Tumor Microenvironment - drug effects; Tumor Microenvironment - physiology; Vaccination
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-01279-1

In this study, we evaluated the consequences of reducing Galectin-1 (Gal-1) in the tumor micro-environment (TME) of glioblastoma multiforme (GBM), via nose-to-brain transport. Gal-1 is overexpressed in GBM and drives chemo- and immunotherapy resistance. To promote nose-to-brain transport, we designed siRNA targeting Gal-1 (siGal-1) loaded chitosan nanoparticles that silence Gal-1 in the TME. Intranasal siGal-1 delivery induces a remarkable switch in the TME composition, with reduced myeloid suppressor cells and regulatory T cells, and increased CD4+ and CD8+ T cells. Gal-1 knock-down reduces macrophages' polarization switch from M1 (pro-inflammatory) to M2 (anti-inflammatory) during GBM progression. These changes are accompanied by normalization of the tumor vasculature and increased survival for tumor bearing mice. The combination of siGal-1 treatment with temozolomide or immunotherapy (dendritic cell vaccination and PD-1 blocking) displays synergistic effects, increasing the survival of tumor bearing mice. Moreover, we could confirm the role of Gal-1 on lymphocytes in GBM patients by matching the Gal-1 expression and their T cell signatures. These findings indicate that intranasal siGal-1 nanoparticle delivery could be a valuable adjuvant treatment to increase the efficiency of immune-checkpoint blockade and chemotherapy.