University of Veterinary Medicine Vienna Fibrolytic vaccination against ADAM12 reduces desmoplasia in preclinical pancreatic adenocarcinomas 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. en TEXT journal article Wissenschaftlicher Artikel Text journal article Text Wissenschaftlicher Artikel 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 2024 2024 Jing Chen Michal Sobecki Ewelina Krzywinska Kevin Thierry Mélissa Masmoudi Shunmugam Nagarajan Zheng Fan Jingyi He Irina Ferapontova Eric Nelius Frauke Seehusen Dagmar Gotthardt Norihiko Takeda Lukas Sommer Veronika Sexl Christian Münz David DeNardo Ana Hennino Christian Stockmann Springer Nature