Jing Chen Jing Chen Michal Sobecki Michal Sobecki Ewelina Krzywinska Ewelina Krzywinska Kevin Thierry Kevin Thierry Mélissa Masmoudi Mélissa Masmoudi Shunmugam Nagarajan Shunmugam Nagarajan Zheng Fan Zheng Fan Jingyi He Jingyi He Irina Ferapontova Irina Ferapontova Eric Nelius Eric Nelius Frauke Seehusen Frauke Seehusen Dagmar Gotthardt Dagmar Gotthardt Norihiko Takeda Norihiko Takeda Lukas Sommer Lukas Sommer Veronika Sexl Veronika Sexl Christian Münz Christian Münz David DeNardo David DeNardo Ana Hennino Ana Hennino Christian Stockmann Christian Stockmann Springer Nature 2024 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. PDFDocument eng 2025-01-20T08:44:45.061362Z 2024 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 15323446 b application/pdf application/pdf http://creativecommons.org/licenses/by/4.0/