Fibrolytic vaccination against ADAM12 reduces desmoplasia in preclinical pancreatic adenocarcinomas
Uloženo v:
| Název: | Fibrolytic vaccination against ADAM12 reduces desmoplasia in preclinical pancreatic adenocarcinomas |
|---|---|
| Autoři: | Chen, Jing, Sobecki, Michal, Krzywinska, Ewelina, Thierry, Kevin, Masmoudi, Mélissa, Nagarajan, Shunmugam, Fan, Zheng, He, Jingyi, Ferapontova, Irina, Nelius, Eric, Seehusen, Frauke, Gotthardt, Dagmar, Takeda, Norihiko, Sommer, Lukas, Sexl, Veronika, Münz, Christian, DeNardo, David, Hennino, Ana, Stockmann, Christian |
| Přispěvatelé: | University of Zurich, Stockmann, Christian |
| Zdroj: | EMBO Mol Med EMBO Molecular Medicine, Vol 16, Iss 12, Pp 3033-3056 (2024) |
| Informace o vydavateli: | Springer Science and Business Media LLC, 2024. |
| Rok vydání: | 2024 |
| Témata: | Cancer-Associated Fibroblasts Immunology, Medicine (General), Adenocarcinoma Immunology, 10017 Institute of Anatomy, Cancer-Associated Fibroblasts Pathology, 10184 Institute of Veterinary Pathology, ADAM12 Protein Metabolism, Pancreatic Neoplasms Prevention & Control, ADAM12 Protein, 610 Medicine & health, QH426-470, CD8-Positive T-Lymphocytes, Adenocarcinoma, 10263 Institute of Experimental Immunology, Cancer Vaccines, Mice, CD8-Positive T-Lymphocytes Immunology, R5-920, Cancer-Associated Fibroblasts, Report, Carcinoma, Pancreatic Ductal Pathology, Genetics, Mice Inbred C57BL, Adenocarcinoma Pathology, Animals, Humans, Cancer Vaccines Immunology, Pancreatic Adenocarcinoma, Cancer Vaccines Administration & Dosage, Cancer-Associated Fibroblasts Metabolism, Disease Models Animal, Vaccination, Fibrosis, Pancreatic Neoplasms, Mice, Inbred C57BL, Disease Models, Animal, Pancreatic Neoplasms Immunology, 1313 Molecular Medicine, 11401 Comprehensive Cancer Center Zurich, Pancreatic Neoplasms Pathology, Carcinoma Pancreatic Ductal Therapy, Adenocarcinoma Therapy, 570 Life sciences, biology, Immunotherapy, Carcinoma Pancreatic Ductal Immunology, Carcinoma, Pancreatic Ductal |
| Popis: | A hallmark feature of pancreatic ductal adenocarcinoma (PDAC) is massive intratumoral fibrosis, designated as desmoplasia. Desmoplasia is characterized by the expansion of cancer-associated fibroblasts (CAFs) and a massive increase in extracellular matrix (ECM). During fibrogenesis, distinct genes become reactivated specifically in fibroblasts, e.g., the disintegrin metalloprotease, ADAM12. Previous studies have shown that immunotherapeutic ablation of ADAM12+ cells reduces fibrosis in various organs. In preclinical mouse models of PDAC, we observe ADAM12 expression in CAFs as well as in tumor cells but not in healthy mouse pancreas. Therefore, we tested prophylactic and therapeutic vaccination against ADAM12 in murine PDAC and observed delayed tumor growth along with a reduction in CAFs and tumor desmoplasia. This is furthermore associated with vascular normalization and alleviated tumor hypoxia. The ADAM12 vaccine induces a redistribution of CD8+ T cells within the tumor and cytotoxic responses against ADAM12+ cells. In summary, vaccination against the endogenous fibroblast target ADAM12 effectively depletes CAFs, reduces desmoplasia and delays the growth of murine PDACs. These results provide proof-of-principle for the development of vaccination-based immunotherapies to treat tumor desmoplasia. |
| Druh dokumentu: | Article Other literature type |
| Popis souboru: | application/pdf; chen_et_al_2024_fibrolytic_vaccination_against_adam12_reduces_desmoplasia_in_preclinical_pancreatic_adenocarcinomas.pdf - application/pdf |
| Jazyk: | English |
| ISSN: | 1757-4684 |
| DOI: | 10.1038/s44321-024-00157-4 |
| DOI: | 10.5167/uzh-264242 |
| Přístupová URL adresa: | https://pubmed.ncbi.nlm.nih.gov/39478152 https://doaj.org/article/32a6bfacd9884de49c5ed19adffba64c https://phaidra.vetmeduni.ac.at/o:3794 https://doi.org/10.1038/s44321-024-00157-4 |
| Rights: | CC BY URL: http://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (http://creativecommons.org/licenses/by/4.0/) . Creative Commons Public Domain Dedication waiver http://creativecommons.org/publicdomain/zero/1.0/ (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data associated with this article, unless otherwise stated in a credit line to the data, but does not extend to the graphical or creative elements of illustrations, charts, or figures. This waiver removes legal barriers to the re-use and mining of research data. According to standard scholarly practice, it is recommended to provide appropriate citation and attribution whenever technically possible. |
| Přístupové číslo: | edsair.doi.dedup.....71ecefac590becc4424aa8f5c0456478 |
| Databáze: | OpenAIRE |
Full Text 
Full Text Finder 
Nájsť tento článok vo Web of Science | Abstrakt: | A hallmark feature of pancreatic ductal adenocarcinoma (PDAC) is massive intratumoral fibrosis, designated as desmoplasia. Desmoplasia is characterized by the expansion of cancer-associated fibroblasts (CAFs) and a massive increase in extracellular matrix (ECM). During fibrogenesis, distinct genes become reactivated specifically in fibroblasts, e.g., the disintegrin metalloprotease, ADAM12. Previous studies have shown that immunotherapeutic ablation of ADAM12+ cells reduces fibrosis in various organs. In preclinical mouse models of PDAC, we observe ADAM12 expression in CAFs as well as in tumor cells but not in healthy mouse pancreas. Therefore, we tested prophylactic and therapeutic vaccination against ADAM12 in murine PDAC and observed delayed tumor growth along with a reduction in CAFs and tumor desmoplasia. This is furthermore associated with vascular normalization and alleviated tumor hypoxia. The ADAM12 vaccine induces a redistribution of CD8+ T cells within the tumor and cytotoxic responses against ADAM12+ cells. In summary, vaccination against the endogenous fibroblast target ADAM12 effectively depletes CAFs, reduces desmoplasia and delays the growth of murine PDACs. These results provide proof-of-principle for the development of vaccination-based immunotherapies to treat tumor desmoplasia. |
|---|---|
| ISSN: | 17574684 |
| DOI: | 10.1038/s44321-024-00157-4 |