Intratumoral Delivery of TriMix mRNA Results in T-cell Activation by Cross-Presenting Dendritic Cells
| Autor: | Sandra Van Lint, Stephanie Du Four, Véronique Flamand, Karine Breckpot, Kevin Van der Jeught, Lukasz Bialkowski, Cleo Goyvaerts, Sarah Maenhout, Lode Goethals, Daphné Benteyn, Dries Renmans, Kris Thielemans, Katleen Broos, Carlo Heirman |
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| Přispěvatelé: | Laboratory of Molecullar and Cellular Therapy, Basic (bio-) Medical Sciences, Faculty of Medicine and Pharmacy, Medical Imaging, Supporting clinical sciences, Clinical sciences, Physiology, Immunomodulation in Chronic Inflammatory Diseases |
| Rok vydání: | 2016 |
| Předmět: |
Cytotoxicity
Immunologic 0301 basic medicine Cancer Research T-Lymphocytes T cell medicine.medical_treatment CD40 Ligand Immunology T-Cell Antigen Receptor Specificity Lymphocyte Activation Mice 03 medical and health sciences Cross-Priming Antigen Cancer immunotherapy Cell Line Tumor Neoplasms medicine Animals RNA Messenger Receptor CD70 CD40 biology Electroporation Dendritic Cells Toll-Like Receptor 4 Disease Models Animal Phenotype 030104 developmental biology medicine.anatomical_structure Cell culture biology.protein Cancer research Female Biomarkers CD27 Ligand |
| Zdroj: | Cancer Immunology Research. 4:146-156 |
| ISSN: | 2326-6074 2326-6066 |
| DOI: | 10.1158/2326-6066.cir-15-0163 |
| Popis: | Modulating the activity of tumor-infiltrating dendritic cells (TiDC) provides opportunities for novel cancer interventions. In this article, we report on our study of the uptake of mRNA by CD8α+ cross-presenting TiDCs upon its intratumoral (i.t.) delivery. We exploited this property to deliver mRNA encoding the costimulatory molecule CD70, the activation stimuli CD40 ligand, and constitutively active Toll-like receptor 4, referred to as TriMix mRNA. We show that TiDCs are reprogrammed to mature antigen-presenting cells that migrate to tumor-draining lymph nodes (TDLN). TriMix stimulated antitumor T-cell responses to spontaneously engulfed cancer antigens, including a neoepitope. We show in various mouse cancer models that i.t. delivery of TriMix mRNA results in systemic therapeutic antitumor immunity. Finally, we show that the induction of antitumor responses critically depends on TiDCs, whereas it only partially depends on TDLNs. As such, we provide a platform and a mechanistic rationale for the clinical testing of i.t. administration of TriMix mRNA. Cancer Immunol Res; 4(2); 146–56. ©2015 AACR. |
| Databáze: | OpenAIRE |
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