Dual-adjuvant effect of pH-sensitive liposomes loaded with STING and TLR9 agonists regress tumor development by enhancing Th1 immune response
| Autor: | Kubra Almacioglu, Ihsan Gursel, Banu Bayyurt Kocabas, Gozde Gucluler, Esin Alpdundar Bulut, Mayda Gursel, Gizem Tincer, Defne Bayik |
|---|---|
| Přispěvatelé: | Bayyurt-Kocabaş, Banu, Almacıoğlu, Kübra, Güçlüler, Gözde, Tincer, Gizem, Gürsel, İhsan |
| Rok vydání: | 2020 |
| Předmět: |
CpG ODN
Ovalbumin CpG Oligodeoxynucleotide medicine.medical_treatment Pharmaceutical Science Cancer immunotherapy 02 engineering and technology CD8-Positive T-Lymphocytes Mice 03 medical and health sciences Immune system Adjuvants Immunologic Antigen medicine Animals 030304 developmental biology 0303 health sciences Tumor microenvironment Chemistry Immunity Pattern recognition receptor Hydrogen-Ion Concentration 021001 nanoscience & nanotechnology Immune-adjuvant synergy Mice Inbred C57BL pH-sensitive liposome Oligodeoxyribonucleotides Toll-Like Receptor 9 cGAMP Liposomes Drug delivery Cancer research 0210 nano-technology Adjuvant |
| Zdroj: | Journal of Controlled Release |
| ISSN: | 0168-3659 |
| Popis: | Nucleic acid-based pattern recognition receptor agonists are effective adjuvants and immunotherapeutic agents. Rather than single applications, ligand combinations could synergistically potentiate immune responses by elevating cytokine and chemokine production via triggering multiple signaling pathways. However, short half-lives of such labile ligands due to nuclease attack and limited cellular uptake due to their structure significantly hamper their in vivo performances. More importantly, simultaneous delivery and activity presentation of protein antigen and nucleic acid ligands critically limit the clinical development of these constructs. In this work, we approached this problem by co-encapsulating a model antigen ovalbumin along with TLR9 and STING ligands within liposomes, a well-established drug delivery system that enables payload stability and enhanced cellular activity upon internalization. Moreover, by loading dual ligands we postulated to achieve heightened Th-1 immune response that would yield pronounced protective vaccine efficacy. We show that, pH-sensitive liposomes co-encapsulating CpG ODN and cGAMP induced synergistic innate immune response by elevating type I and type II interferon levels. Most importantly, this vaccine formulation led to ~70% regression of established melanoma tumor. pH-sensitive liposomal vaccine administration elevated IgG2c/IgG1 antibody ratio, indicative of augmented OVA-specific Th1-biased immunity. Importantly, while the frequency of tumor-specific IFN-γ producing CD8+ T-cells was significantly increased, the M2-type anti-inflammatory macrophage levels were decreased in the tumor bed. In conclusion, our strategy induces reversal of immunosuppressive tumor microenvironment, while enhancing effective anti-tumor immune-response. We propose that this could be coupled with standard therapies during combating tumor eradication. This work was partially supported by Scientific and Technological Research Council of Turkey (TUBITAK, Grant #: SBAG-113S207 to I.G.), and Ministry of Development (Grant name: UMRAM-ASI, Project #: 2015BSV302 to I.G.). |
| Databáze: | OpenAIRE |
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