ATP128 Clinical Therapeutic Cancer Vaccine Activates NF-κB and IRF3 Pathways through TLR4 and TLR2 in Human Monocytes and Dendritic Cells
The use of cancer vaccines is a promising therapeutic strategy able to stimulate anti-tumor immunity by inducing both humoral and cellular immunity. In this study, antigen presenting cells play a key role by inducing a strong activation of the T cell-mediated adaptive immune response, essential for...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-10-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/20/5134 |
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| author | Roberta Pascolutti Lakshmi Yeturu Géraldine Philippin Stéphane Costa Borges Magali Dejob Marie-Laure Santiago-Raber Madiha Derouazi |
| author_facet | Roberta Pascolutti Lakshmi Yeturu Géraldine Philippin Stéphane Costa Borges Magali Dejob Marie-Laure Santiago-Raber Madiha Derouazi |
| author_sort | Roberta Pascolutti |
| collection | DOAJ |
| description | The use of cancer vaccines is a promising therapeutic strategy able to stimulate anti-tumor immunity by inducing both humoral and cellular immunity. In this study, antigen presenting cells play a key role by inducing a strong activation of the T cell-mediated adaptive immune response, essential for the anti-tumor potential of cancer vaccines. The first human candidate vaccine created from the KISIMA platform, ATP128, bears three tumor-associated antigens highly expressed in colorectal cancer tissues. At the N-terminus, the cell-penetrating peptide allows the antigen delivery inside the cell and, together with the TLR agonist-derived peptide at the C-terminus, ensures the activation of the monocyte-derived dendritic cells. Here, we show that ATP128 leads to both NF-κB and IRF3 pathway activation, with subsequent pro-inflammatory cytokines and type I Interferon release, as well as an increase in the expression of costimulatory molecules, alongside an upregulation of MHC class I molecules. This cellular immune response involves TLR2 and TLR4, for both membrane and intracellular signaling. We demonstrated an endocytic component in ATP128’s activity by combining the use of a variant of ATP128 lacking the cell-penetrating peptide with endocytosis inhibitors. Importantly, this internalization step is detemined essential for the activation of the IRF3 pathway. This study validates the design of the self-adjuvanting ATP128 vaccine for cancer immunotherapy. |
| first_indexed | 2024-03-09T20:31:28Z |
| format | Article |
| id | doaj.art-cc990661f5fe40d999feba580ab06df4 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T20:31:28Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-cc990661f5fe40d999feba580ab06df42023-11-23T23:22:32ZengMDPI AGCancers2072-66942022-10-011420513410.3390/cancers14205134ATP128 Clinical Therapeutic Cancer Vaccine Activates NF-κB and IRF3 Pathways through TLR4 and TLR2 in Human Monocytes and Dendritic CellsRoberta Pascolutti0Lakshmi Yeturu1Géraldine Philippin2Stéphane Costa Borges3Magali Dejob4Marie-Laure Santiago-Raber5Madiha Derouazi6AMAL Therapeutics, 1205 Geneva, SwitzerlandAMAL Therapeutics, 1205 Geneva, SwitzerlandAMAL Therapeutics, 1205 Geneva, SwitzerlandAMAL Therapeutics, 1205 Geneva, SwitzerlandAMAL Therapeutics, 1205 Geneva, SwitzerlandAMAL Therapeutics, 1205 Geneva, SwitzerlandAMAL Therapeutics, 1205 Geneva, SwitzerlandThe use of cancer vaccines is a promising therapeutic strategy able to stimulate anti-tumor immunity by inducing both humoral and cellular immunity. In this study, antigen presenting cells play a key role by inducing a strong activation of the T cell-mediated adaptive immune response, essential for the anti-tumor potential of cancer vaccines. The first human candidate vaccine created from the KISIMA platform, ATP128, bears three tumor-associated antigens highly expressed in colorectal cancer tissues. At the N-terminus, the cell-penetrating peptide allows the antigen delivery inside the cell and, together with the TLR agonist-derived peptide at the C-terminus, ensures the activation of the monocyte-derived dendritic cells. Here, we show that ATP128 leads to both NF-κB and IRF3 pathway activation, with subsequent pro-inflammatory cytokines and type I Interferon release, as well as an increase in the expression of costimulatory molecules, alongside an upregulation of MHC class I molecules. This cellular immune response involves TLR2 and TLR4, for both membrane and intracellular signaling. We demonstrated an endocytic component in ATP128’s activity by combining the use of a variant of ATP128 lacking the cell-penetrating peptide with endocytosis inhibitors. Importantly, this internalization step is detemined essential for the activation of the IRF3 pathway. This study validates the design of the self-adjuvanting ATP128 vaccine for cancer immunotherapy.https://www.mdpi.com/2072-6694/14/20/5134therapeutic cancer vaccineself-adjuvanticitytoll-like receptor 2toll-like receptor 4dendritic cells activation |
| spellingShingle | Roberta Pascolutti Lakshmi Yeturu Géraldine Philippin Stéphane Costa Borges Magali Dejob Marie-Laure Santiago-Raber Madiha Derouazi ATP128 Clinical Therapeutic Cancer Vaccine Activates NF-κB and IRF3 Pathways through TLR4 and TLR2 in Human Monocytes and Dendritic Cells Cancers therapeutic cancer vaccine self-adjuvanticity toll-like receptor 2 toll-like receptor 4 dendritic cells activation |
| title | ATP128 Clinical Therapeutic Cancer Vaccine Activates NF-κB and IRF3 Pathways through TLR4 and TLR2 in Human Monocytes and Dendritic Cells |
| title_full | ATP128 Clinical Therapeutic Cancer Vaccine Activates NF-κB and IRF3 Pathways through TLR4 and TLR2 in Human Monocytes and Dendritic Cells |
| title_fullStr | ATP128 Clinical Therapeutic Cancer Vaccine Activates NF-κB and IRF3 Pathways through TLR4 and TLR2 in Human Monocytes and Dendritic Cells |
| title_full_unstemmed | ATP128 Clinical Therapeutic Cancer Vaccine Activates NF-κB and IRF3 Pathways through TLR4 and TLR2 in Human Monocytes and Dendritic Cells |
| title_short | ATP128 Clinical Therapeutic Cancer Vaccine Activates NF-κB and IRF3 Pathways through TLR4 and TLR2 in Human Monocytes and Dendritic Cells |
| title_sort | atp128 clinical therapeutic cancer vaccine activates nf κb and irf3 pathways through tlr4 and tlr2 in human monocytes and dendritic cells |
| topic | therapeutic cancer vaccine self-adjuvanticity toll-like receptor 2 toll-like receptor 4 dendritic cells activation |
| url | https://www.mdpi.com/2072-6694/14/20/5134 |
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