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Intracellularly-Targeted Nanoplatform to Target Dendritic Cells and for Immunomodulation
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Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Immunotherapy, notably cancer vaccines and immune checkpoint modulators, has emerged as a promising alternative therapy. However, limited efficacy has been obtained for cancer vaccines and severe immune-mediated side effects have been related to immune checkpoint inhibitors under clinical development. Thus, to overcome the main disadvantages presented by these two therapeutic options when used individually, and considering the heterogeneity of TNBC, combination therapies are under clinical development to treat this specific breast cancer subtype.
We hypothesized that the development of a multifunctional nanovaccine could re-shape the tumour microenvironment (TME), sensitizing TNBC to the agonist immune checkpoint OX40, and thus, improving the overall anti-tumour immune response.
For this purpose, a poly(lactic acid) (PLA) nanoparticle (NP)-based nanovaccine was designed and synthesized to target dendritic cells (DC) and the TME by incorporating TNBC-associated antigens, toll-like receptor ligands CpG and Poly(I:C), and siRNA to downregulate the potent immunosuppressive cytokine transforming growth factor-β (TGF-β). NP surface was modified by hyaluronic acid to promote DC activation, but also to potentiate their delivery to the TME by targeting CD44 receptor, overexpressed in TNBC cells.
NPs presented a spherical-shape with an average diameter close to 200 nm, displaying narrow polydispersity index, near-neutral surface charge, and entrapment efficiencies (EE) superior to 85%. NPs were extensively taken up by both DC and TNBC cells, without affecting their viability. In addition, NPs induced DC activation and maturation, increasing significantly the expression of the surface markers. 4T1 tumour-bearing animals treated with the multifunctional nanovaccine combined with αOX40 showed a noteworthy tumour remission, with a higher overall survival and a tumour volume 4-fold lower than those obtained for αOX40-treated mice. The nanovaccine re-shaped the immune profiling within the TME, which correlated with the overall anti-tumour effect obtained in this combinatorial scheme. This study revealed the synergy between a multi-targeting nanovaccine and αOX40 in TNBC, providing important insights for the establishment of novel combination regimens against this tumour.
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vaccine triple-negative breast cancer nanomedicine tumour microenvironment immune checkpoints