https://phaidra.vetmeduni.ac.at/o:3794 Fibrolytic vaccination against ADAM12 reduces desmoplasia in preclinical pancreatic adenocarcinomas Chen, Jing Jing Chen 0000-0003-1835-2373 Sobecki, Michal Michal Sobecki Krzywinska, Ewelina Ewelina Krzywinska Thierry, Kevin Kevin Thierry 0000-0003-0123-3124 Masmoudi, Mélissa Mélissa Masmoudi 0009-0006-2426-2621 Nagarajan, Shunmugam Shunmugam Nagarajan Fan, Zheng Zheng Fan He, Jingyi Jingyi He 0000-0002-3640-3093 Ferapontova, Irina Irina Ferapontova Nelius, Eric Eric Nelius Seehusen, Frauke Frauke Seehusen Gotthardt, Dagmar Dagmar Gotthardt 0000-0002-8416-1236 Takeda, Norihiko Norihiko Takeda Sommer, Lukas Lukas Sommer 0000-0002-1143-7908 Sexl, Veronika Veronika Sexl 0000-0001-9363-0412 Münz, Christian Christian Münz 0000-0001-6419-1940 DeNardo, David David DeNardo Hennino, Ana Ana Hennino 0000-0002-2619-8559 Stockmann, Christian Christian Stockmann 0000-0002-9726-6838 Springer Nature journal article open access eng 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. Animals ADAM12 Protein Metabolism Mice Cancer Vaccines Immunology Cancer Vaccines Administration & Dosage Pancreatic Neoplasms Pathology Pancreatic Neoplasms Immunology Pancreatic Neoplasms Prevention & Control Carcinoma Pancreatic Ductal Immunology Carcinoma, Pancreatic Ductal Pathology Carcinoma Pancreatic Ductal Therapy Vaccination Disease Models Animal Mice Inbred C57BL Cancer-Associated Fibroblasts Metabolism Cancer-Associated Fibroblasts Pathology Cancer-Associated Fibroblasts Immunology Humans CD8-Positive T-Lymphocytes Immunology Fibrosis Adenocarcinoma Immunology Adenocarcinoma Pathology Adenocarcinoma Therapy http://creativecommons.org/licenses/by/4.0/ https://phaidra.vetmeduni.ac.at/api/object/o:3794/download 10.1038/s44321-024-00157-4 https://phaidra.vetmeduni.ac.at/o:605 application/pdf EMBO Molecular Medicine issn:1757-4684 VoR EMBO Molecular Medicine 1116 12 14.61 MB 2024