Ahmed E. I. Hamouda, Jessica Filtjens, Elisabeth Brabants, Daliya Kancheva, Ayla Debraekeleer, Jan Brughmans, Lotte Jacobs, Pauline M. R. Bardet, Elisabeth Knetemann, Pierre Lefesvre, Lize Allonsius, Mark Gontsarik, Ismael Varela, Marian Crabbé, Emile J. Clappaert, Federica Cappellesso, Aarushi A. Caro, Alícia Gordún Peiró, Luna Fredericq, Eva Hadadi, Mariona Estapé Senti, Raymond Schiffelers, Leo A. van Grunsven, Frank Aboubakar Nana, Bruno G. De Geest, Sofie Deschoemaeker, Stefaan De Koker, Florence Lambolez, Damya Laoui
{"title":"Intratumoral delivery of lipid nanoparticle-formulated mRNA encoding IL-21, IL-7, and 4-1BBL induces systemic anti-tumor immunity","authors":"Ahmed E. I. Hamouda, Jessica Filtjens, Elisabeth Brabants, Daliya Kancheva, Ayla Debraekeleer, Jan Brughmans, Lotte Jacobs, Pauline M. R. Bardet, Elisabeth Knetemann, Pierre Lefesvre, Lize Allonsius, Mark Gontsarik, Ismael Varela, Marian Crabbé, Emile J. Clappaert, Federica Cappellesso, Aarushi A. Caro, Alícia Gordún Peiró, Luna Fredericq, Eva Hadadi, Mariona Estapé Senti, Raymond Schiffelers, Leo A. van Grunsven, Frank Aboubakar Nana, Bruno G. De Geest, Sofie Deschoemaeker, Stefaan De Koker, Florence Lambolez, Damya Laoui","doi":"10.1038/s41467-024-54877-9","DOIUrl":null,"url":null,"abstract":"<p>Local delivery of mRNA-based immunotherapy offers a promising avenue as it enables the production of specific immunomodulatory proteins that can stimulate the immune system to recognize and eliminate cancer cells while limiting systemic exposure and toxicities. Here, we develop and employ lipid-based nanoparticles (LNPs) to intratumorally deliver an mRNA mixture encoding the cytokines interleukin (IL)−21 and IL-7 and the immunostimulatory molecule 4-1BB ligand (Triplet LNP). IL-21 synergy with IL-7 and 4-1BBL leads to a profound increase in the frequency of tumor-infiltrating CD8<sup>+</sup> T cells and their capacity to produce granzyme B and IFN-γ, leading to tumor eradication and the development of long-term immunological memory. Mechanistically, the efficacy of the Triplet LNP depends on tumor-draining lymph nodes to tumor CD8<sup>+</sup> T-cell trafficking. Moreover, we highlight the therapeutic potential of the Triplet LNP in multiple tumor models in female mice and its superior therapeutic efficacy to immune checkpoint blockade. Ultimately, the expression of these immunomodulators is associated with better overall survival in patients with cancer.</p>","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"38 1","pages":""},"PeriodicalIF":14.7000,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature Communications","FirstCategoryId":"103","ListUrlMain":"https://doi.org/10.1038/s41467-024-54877-9","RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}
引用次数: 0
Abstract
Local delivery of mRNA-based immunotherapy offers a promising avenue as it enables the production of specific immunomodulatory proteins that can stimulate the immune system to recognize and eliminate cancer cells while limiting systemic exposure and toxicities. Here, we develop and employ lipid-based nanoparticles (LNPs) to intratumorally deliver an mRNA mixture encoding the cytokines interleukin (IL)−21 and IL-7 and the immunostimulatory molecule 4-1BB ligand (Triplet LNP). IL-21 synergy with IL-7 and 4-1BBL leads to a profound increase in the frequency of tumor-infiltrating CD8+ T cells and their capacity to produce granzyme B and IFN-γ, leading to tumor eradication and the development of long-term immunological memory. Mechanistically, the efficacy of the Triplet LNP depends on tumor-draining lymph nodes to tumor CD8+ T-cell trafficking. Moreover, we highlight the therapeutic potential of the Triplet LNP in multiple tumor models in female mice and its superior therapeutic efficacy to immune checkpoint blockade. Ultimately, the expression of these immunomodulators is associated with better overall survival in patients with cancer.
期刊介绍:
Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.