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.

Keywords (eng)

AnimalsADAM12 Protein MetabolismMiceCancer Vaccines ImmunologyCancer Vaccines Administration & DosagePancreatic Neoplasms PathologyPancreatic Neoplasms ImmunologyPancreatic Neoplasms Prevention & ControlCarcinoma Pancreatic Ductal ImmunologyCarcinoma, Pancreatic Ductal PathologyCarcinoma Pancreatic Ductal TherapyVaccinationDisease Models AnimalMice Inbred C57BLCancer-Associated Fibroblasts MetabolismCancer-Associated Fibroblasts PathologyCancer-Associated Fibroblasts ImmunologyHumansCD8-Positive T-Lymphocytes ImmunologyFibrosisAdenocarcinoma ImmunologyAdenocarcinoma PathologyAdenocarcinoma Therapy

Type (eng)

journal article

Language

[eng]

Persistent identifier

https://phaidra.vetmeduni.ac.at/o:3794

DOI

10.1038/s44321-024-00157-4

Is in series

Title (eng)

EMBO Molecular Medicine

Volume