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. Synopsis ADAM12, a disintegrin and metalloprotease, is expressed in cancer-associated fibroblasts (CAFs) and tumor cells in pancreatic ductal adenocarcinoma (PDAC). Using both subcutaneous and orthotopic PDAC mouse models, we show that vaccination against ADAM12 depletes CAFs and delays tumor growth. ADAM12 vaccination induced a reduction of ADAM12+ CAFs, and decreased deposition of extracellular matrix (ECM). ADAM12 vaccination increased cytotoxic CD8 + T cell response and re-localization of T cells within the tumor tissue. ADAM12 vaccination induced vascular normalization with decreased tumor hypoxia. This study constitutes a proof of principle for the development of vaccination-based immunotherapies to target CAFs and tumor desmoplasia. ADAM12, a disintegrin and metalloprotease, is expressed in cancer-associated fibroblasts (CAFs) and tumor cells in pancreatic ductal adenocarcinoma (PDAC). Using both subcutaneous and orthotopic PDAC mouse models, we show that vaccination against ADAM12 depletes CAFs and delays tumor growth.