Nanostructured lipid carriers based mRNA vaccine leads to a T cell–inflamed tumour microenvironment favourable for improving PD-1/PD-L1 blocking therapy and long-term immunity in a cold tumour modelResearch in context
Summary: Background: mRNA-based cancer vaccines show promise in triggering antitumour immune responses. To combine them with existing immunotherapies, the intratumoral immune microenvironment needs to be deeply characterised. Here, we test nanostructured lipid carriers (NLCs), the so-called Lipidot...
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Elsevier
2025-02-01
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| Series: | EBioMedicine |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396424005796 |
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| author | Carole Fournier Marion Mercey-Ressejac Valentin Derangère Amal Al Kadi David Rageot Christine Charrat Alexis Leroy Julien Vollaire Véronique Josserand Marie Escudé Séverine Escaich François Ghiringhelli Thomas Decaens Fabrice P. Navarro Evelyne Jouvin-Marche Patrice N. Marche |
| author_facet | Carole Fournier Marion Mercey-Ressejac Valentin Derangère Amal Al Kadi David Rageot Christine Charrat Alexis Leroy Julien Vollaire Véronique Josserand Marie Escudé Séverine Escaich François Ghiringhelli Thomas Decaens Fabrice P. Navarro Evelyne Jouvin-Marche Patrice N. Marche |
| author_sort | Carole Fournier |
| collection | DOAJ |
| description | Summary: Background: mRNA-based cancer vaccines show promise in triggering antitumour immune responses. To combine them with existing immunotherapies, the intratumoral immune microenvironment needs to be deeply characterised. Here, we test nanostructured lipid carriers (NLCs), the so-called Lipidots®, for delivering unmodified mRNA encoding Ovalbumin (OVA) antigen to elicit specific antitumour responses. Methods: We evaluated whether NLC OVA mRNA complexes activate dendritic cells (DCs) in vitro and identified the involved signalling pathways using specific inhibitors. We tested the anti-tumoral impact of Ova mRNA vaccine in B16-OVA and E.G7-OVA cold tumour-bearing C57Bl6 female mice as well as its synergy effect with an anti-PD-1 therapy by following the tumour growth and performing immunophenotyping of innate and adaptive immune cells. The intratumoral vaccine-related gene signature was assessed by RNA-sequencing. The immune memory response was assessed by re-challenging surviving treated mice with tumour cells. Findings: Our vaccine activates DCs in vitro through the TLR4/8 and ROS signalling pathways and induces specific T cell activation while exhibits significant preventive and therapeutic antitumour efficacy in vivo. A profound intratumoral remodelling of the innate and adaptive immunity in association with an increase in the gene expression of chemokines (Cxcl10, Cxcl11, Cxcl9) involved in CD8+ T cell attraction were observed in immunised mice. The combination of vaccine and anti-PD-1 therapy improves the rates of complete responses and memory immune responses compared to monotherapies. Interpretation: Lipidots® are effective platform for the development of vaccines against cancer based on mRNA delivery. Their combination with immune checkpoint blockers could counter tumour resistance and promote long-term antitumour immunity. Funding: This work was supported by Inserm Transfert, la Région Auvergne Rhône Alpes, FINOVI, and the French Ministry of Higher Education, research and innovation (LipiVAC, COROL project, funding reference N° 2102992411). |
| format | Article |
| id | doaj-art-c28598e7e4924e1f91807fac8e914fe6 |
| institution | Kabale University |
| issn | 2352-3964 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj-art-c28598e7e4924e1f91807fac8e914fe62025-01-11T06:41:34ZengElsevierEBioMedicine2352-39642025-02-01112105543Nanostructured lipid carriers based mRNA vaccine leads to a T cell–inflamed tumour microenvironment favourable for improving PD-1/PD-L1 blocking therapy and long-term immunity in a cold tumour modelResearch in contextCarole Fournier0Marion Mercey-Ressejac1Valentin Derangère2Amal Al Kadi3David Rageot4Christine Charrat5Alexis Leroy6Julien Vollaire7Véronique Josserand8Marie Escudé9Séverine Escaich10François Ghiringhelli11Thomas Decaens12Fabrice P. Navarro13Evelyne Jouvin-Marche14Patrice N. Marche15Univ. Grenoble Alpes, Institute for Advanced Biosciences, Inserm U 1209, CNRS UMR, Grenoble, 5309, France; Hepato-Gastroenterology and Digestive Oncology Department, CHU Grenoble Alpes, Grenoble, France; Corresponding author. Univ. Grenoble Alpes, Institute for Advanced Biosciences, Inserm U 1209, CNRS UMR, Grenoble, 5309, France.Univ. Grenoble Alpes, Institute for Advanced Biosciences, Inserm U 1209, CNRS UMR, Grenoble, 5309, FranceINSERM U1231, Equipe TIRECS, Dijon, 21000, France; Université de Bourgogne, Dijon, 21000, France; Centre de Lutte contre le Cancer Georges François Leclerc, Plateforme de Transfert en Biologie du Cancer, Dijon, 21000, FranceUniv. Grenoble Alpes, Institute for Advanced Biosciences, Inserm U 1209, CNRS UMR, Grenoble, 5309, FranceINSERM U1231, Equipe TIRECS, Dijon, 21000, France; Université de Bourgogne, Dijon, 21000, France; Centre de Lutte contre le Cancer Georges François Leclerc, Plateforme de Transfert en Biologie du Cancer, Dijon, 21000, FranceUniv. Grenoble Alpes, Institute for Advanced Biosciences, Inserm U 1209, CNRS UMR, Grenoble, 5309, FranceUniv. Grenoble Alpes, Institute for Advanced Biosciences, Inserm U 1209, CNRS UMR, Grenoble, 5309, FranceUniv. Grenoble Alpes, Institute for Advanced Biosciences, Inserm U 1209, CNRS UMR, Grenoble, 5309, FranceUniv. Grenoble Alpes, Institute for Advanced Biosciences, Inserm U 1209, CNRS UMR, Grenoble, 5309, FranceCEA, LETI, Technologies for Healthcare and Biology Division, Microtechnologies for Living Systems Interactions Research Unit, Univ. Grenoble Alpes, Grenoble, F-38000, FranceCEA, LETI, Technologies for Healthcare and Biology Division, Microtechnologies for Living Systems Interactions Research Unit, Univ. Grenoble Alpes, Grenoble, F-38000, FranceINSERM U1231, Equipe TIRECS, Dijon, 21000, France; Université de Bourgogne, Dijon, 21000, France; Centre de Lutte contre le Cancer Georges François Leclerc, Plateforme de Transfert en Biologie du Cancer, Dijon, 21000, FranceUniv. Grenoble Alpes, Institute for Advanced Biosciences, Inserm U 1209, CNRS UMR, Grenoble, 5309, France; Hepato-Gastroenterology and Digestive Oncology Department, CHU Grenoble Alpes, Grenoble, FranceCEA, LETI, Technologies for Healthcare and Biology Division, Microtechnologies for Living Systems Interactions Research Unit, Univ. Grenoble Alpes, Grenoble, F-38000, FranceUniv. Grenoble Alpes, Institute for Advanced Biosciences, Inserm U 1209, CNRS UMR, Grenoble, 5309, FranceUniv. Grenoble Alpes, Institute for Advanced Biosciences, Inserm U 1209, CNRS UMR, Grenoble, 5309, FranceSummary: Background: mRNA-based cancer vaccines show promise in triggering antitumour immune responses. To combine them with existing immunotherapies, the intratumoral immune microenvironment needs to be deeply characterised. Here, we test nanostructured lipid carriers (NLCs), the so-called Lipidots®, for delivering unmodified mRNA encoding Ovalbumin (OVA) antigen to elicit specific antitumour responses. Methods: We evaluated whether NLC OVA mRNA complexes activate dendritic cells (DCs) in vitro and identified the involved signalling pathways using specific inhibitors. We tested the anti-tumoral impact of Ova mRNA vaccine in B16-OVA and E.G7-OVA cold tumour-bearing C57Bl6 female mice as well as its synergy effect with an anti-PD-1 therapy by following the tumour growth and performing immunophenotyping of innate and adaptive immune cells. The intratumoral vaccine-related gene signature was assessed by RNA-sequencing. The immune memory response was assessed by re-challenging surviving treated mice with tumour cells. Findings: Our vaccine activates DCs in vitro through the TLR4/8 and ROS signalling pathways and induces specific T cell activation while exhibits significant preventive and therapeutic antitumour efficacy in vivo. A profound intratumoral remodelling of the innate and adaptive immunity in association with an increase in the gene expression of chemokines (Cxcl10, Cxcl11, Cxcl9) involved in CD8+ T cell attraction were observed in immunised mice. The combination of vaccine and anti-PD-1 therapy improves the rates of complete responses and memory immune responses compared to monotherapies. Interpretation: Lipidots® are effective platform for the development of vaccines against cancer based on mRNA delivery. Their combination with immune checkpoint blockers could counter tumour resistance and promote long-term antitumour immunity. Funding: This work was supported by Inserm Transfert, la Région Auvergne Rhône Alpes, FINOVI, and the French Ministry of Higher Education, research and innovation (LipiVAC, COROL project, funding reference N° 2102992411).http://www.sciencedirect.com/science/article/pii/S2352396424005796mRNA vaccineImmune checkpoint inhibitorCancerT cellsInnate immunityMemory immunity |
| spellingShingle | Carole Fournier Marion Mercey-Ressejac Valentin Derangère Amal Al Kadi David Rageot Christine Charrat Alexis Leroy Julien Vollaire Véronique Josserand Marie Escudé Séverine Escaich François Ghiringhelli Thomas Decaens Fabrice P. Navarro Evelyne Jouvin-Marche Patrice N. Marche Nanostructured lipid carriers based mRNA vaccine leads to a T cell–inflamed tumour microenvironment favourable for improving PD-1/PD-L1 blocking therapy and long-term immunity in a cold tumour modelResearch in context EBioMedicine mRNA vaccine Immune checkpoint inhibitor Cancer T cells Innate immunity Memory immunity |
| title | Nanostructured lipid carriers based mRNA vaccine leads to a T cell–inflamed tumour microenvironment favourable for improving PD-1/PD-L1 blocking therapy and long-term immunity in a cold tumour modelResearch in context |
| title_full | Nanostructured lipid carriers based mRNA vaccine leads to a T cell–inflamed tumour microenvironment favourable for improving PD-1/PD-L1 blocking therapy and long-term immunity in a cold tumour modelResearch in context |
| title_fullStr | Nanostructured lipid carriers based mRNA vaccine leads to a T cell–inflamed tumour microenvironment favourable for improving PD-1/PD-L1 blocking therapy and long-term immunity in a cold tumour modelResearch in context |
| title_full_unstemmed | Nanostructured lipid carriers based mRNA vaccine leads to a T cell–inflamed tumour microenvironment favourable for improving PD-1/PD-L1 blocking therapy and long-term immunity in a cold tumour modelResearch in context |
| title_short | Nanostructured lipid carriers based mRNA vaccine leads to a T cell–inflamed tumour microenvironment favourable for improving PD-1/PD-L1 blocking therapy and long-term immunity in a cold tumour modelResearch in context |
| title_sort | nanostructured lipid carriers based mrna vaccine leads to a t cell inflamed tumour microenvironment favourable for improving pd 1 pd l1 blocking therapy and long term immunity in a cold tumour modelresearch in context |
| topic | mRNA vaccine Immune checkpoint inhibitor Cancer T cells Innate immunity Memory immunity |
| url | http://www.sciencedirect.com/science/article/pii/S2352396424005796 |
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