Article Dans Une Revue EMBO Molecular Medicine Année : 2024

Fibrolytic vaccination against ADAM12 reduces desmoplasia in preclinical pancreatic adenocarcinomas

Jing Chen
Michal Sobecki
  • Fonction : Auteur
Ewelina Krzywinska
  • Fonction : Auteur
Kevin Thierry
Mélissa Masmoudi
Shunmugam Nagarajan
  • Fonction : Auteur
Zheng Fan
  • Fonction : Auteur
Jingyi He
Irina Ferapontova
  • Fonction : Auteur
Eric Nelius
  • Fonction : Auteur
Frauke Seehusen
  • Fonction : Auteur
Dagmar Gotthardt
Norihiko Takeda
  • Fonction : Auteur
Lukas Sommer
Veronika Sexl
  • Fonction : Auteur
Christian Münz
David Denardo
  • Fonction : Auteur
Christian Stockmann

Résumé

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.

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Dates et versions

hal-04916183 , version 1 (28-01-2025)

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Jing Chen, Michal Sobecki, Ewelina Krzywinska, Kevin Thierry, Mélissa Masmoudi, et al.. Fibrolytic vaccination against ADAM12 reduces desmoplasia in preclinical pancreatic adenocarcinomas. EMBO Molecular Medicine, 2024, 16, pp.3033 - 3056. ⟨10.1038/s44321-024-00157-4⟩. ⟨hal-04916183⟩
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