Publicação
Hybrid multimodal nanovaccine against colorectal cancer
| Resumo: | Cancer is the second most deadly disease in the world, constituting an unmet medical need. One of the most severe types of cancer is the colorectal cancer (CRC), constituting 6% of all cancers and the third leading cause of cancer death worldwide. Incidence and mortality of CRC have increased in the last decades and this is a disease that spreads quickly throughout the body, enabling tumor metastasis by evading its recognition and eradication by host immune system. It is necessary to deeply characterize the mechanisms underlying this complex process in order to rationally develop new alternative approaches able to reverse, or even prevent, its uncontrolled progression and dissemination. The development of safe and highly immunogenic vaccines to control and eradicate cancer remains one of the most exigent and challenging tasks. Nanoparticle (NP)-based vaccines are promising tools to induce an antigen-specific immune response able to combat tumor development. By prolonging antigen release and extending antigen exposure to antigen presenting cells (APC), nanotechnology based-vaccines will promote the proliferation of tumor-specific cytotoxic T lymphocytes (CTL), thereby increasing anti-tumor efficacy. α-Galactosylceramide (GalCer) is a glycolipid known as an activator of natural killer T (NKT) cells, following its presentation by dendritic cells (DC) to this sub-population of immune cells. The major goal of this study was to evaluate the synergy between GalCer and major histocompatibility complex (MHC) class I and MHC class II CRC-associated peptide antigens (Adpgk MC38 neoantigen peptides) and the Toll-Like Receptor (TLR) ligands, CpG and Poly (I:C), against CRC development. NP-based vaccine is expected to improve the recognition and processing of peptide-based and lipid-based antigens under evaluation, inducing a broad anti-tumor specific T-cell mediated immunity. This nanovaccine was tested in a CRC murine mouse model, alone or combined with the intratumoral administration of this NP entrapping the TLR ligands associated with GalCer (TME-NP), mimicking the clinical settings currently in development. The combination of GalCer with CRC peptides and TLR ligands successfully restrained tumor growth when delivered by our nanovaccine. The tumor volume of mice immunized with the nanovaccine or combined with the TME-NP was lower than this presented by mice immunized with the NP entrapping only the TLR ligands associated with GalCer. The association of the nanovaccine with the TME-NP resulted in an improved infiltration of DC, NK and T lymphocytes, including NKT cells and memory T cells. In addition, splenocytes of these animals secreted higher levels of TNF-α, IFN-γ and IL-2. The combined delivery of the NKT cell agonist with CRC antigens and TLR ligands via this multimodal nanovaccine displayed a synergistic anti-tumor immune-mediated efficacy in MC38 CRC mouse model. Even though, it was also identified the infiltration of myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM). Therefore, the combination of suppressor myeloid-targeted therapies with our multimodal nanovaccine should be considered in order to achieve CRC regression. |
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| Autores principais: | Mateus, Mariana Soares |
| Assunto: | Colorectal cancer Nanovaccines α-Galactosylceramide Natural killer T cells Antigen presenting cells Teses de mestrado - 2019 |
| Ano: | 2019 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso restrito |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | Cancer is the second most deadly disease in the world, constituting an unmet medical need. One of the most severe types of cancer is the colorectal cancer (CRC), constituting 6% of all cancers and the third leading cause of cancer death worldwide. Incidence and mortality of CRC have increased in the last decades and this is a disease that spreads quickly throughout the body, enabling tumor metastasis by evading its recognition and eradication by host immune system. It is necessary to deeply characterize the mechanisms underlying this complex process in order to rationally develop new alternative approaches able to reverse, or even prevent, its uncontrolled progression and dissemination. The development of safe and highly immunogenic vaccines to control and eradicate cancer remains one of the most exigent and challenging tasks. Nanoparticle (NP)-based vaccines are promising tools to induce an antigen-specific immune response able to combat tumor development. By prolonging antigen release and extending antigen exposure to antigen presenting cells (APC), nanotechnology based-vaccines will promote the proliferation of tumor-specific cytotoxic T lymphocytes (CTL), thereby increasing anti-tumor efficacy. α-Galactosylceramide (GalCer) is a glycolipid known as an activator of natural killer T (NKT) cells, following its presentation by dendritic cells (DC) to this sub-population of immune cells. The major goal of this study was to evaluate the synergy between GalCer and major histocompatibility complex (MHC) class I and MHC class II CRC-associated peptide antigens (Adpgk MC38 neoantigen peptides) and the Toll-Like Receptor (TLR) ligands, CpG and Poly (I:C), against CRC development. NP-based vaccine is expected to improve the recognition and processing of peptide-based and lipid-based antigens under evaluation, inducing a broad anti-tumor specific T-cell mediated immunity. This nanovaccine was tested in a CRC murine mouse model, alone or combined with the intratumoral administration of this NP entrapping the TLR ligands associated with GalCer (TME-NP), mimicking the clinical settings currently in development. The combination of GalCer with CRC peptides and TLR ligands successfully restrained tumor growth when delivered by our nanovaccine. The tumor volume of mice immunized with the nanovaccine or combined with the TME-NP was lower than this presented by mice immunized with the NP entrapping only the TLR ligands associated with GalCer. The association of the nanovaccine with the TME-NP resulted in an improved infiltration of DC, NK and T lymphocytes, including NKT cells and memory T cells. In addition, splenocytes of these animals secreted higher levels of TNF-α, IFN-γ and IL-2. The combined delivery of the NKT cell agonist with CRC antigens and TLR ligands via this multimodal nanovaccine displayed a synergistic anti-tumor immune-mediated efficacy in MC38 CRC mouse model. Even though, it was also identified the infiltration of myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM). Therefore, the combination of suppressor myeloid-targeted therapies with our multimodal nanovaccine should be considered in order to achieve CRC regression. |
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