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.

中文翻译：

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针对 ADAM12 的纤维溶解疫苗接种可减少临床前胰腺癌的结纤维增生。


胰腺导管腺癌 （PDAC） 的一个标志性特征是大面积瘤内纤维化，称为结纤维增生。结纤维增生的特征是癌症相关成纤维细胞 （CAF） 的扩增和细胞外基质 （ECM） 的大量增加。在纤维形成过程中，不同的基因在成纤维细胞中被特异性重新激活，例如，解整合素金属蛋白酶 ADAM12。先前的研究表明，ADAM12+ 细胞的免疫治疗消融可减少各种器官的纤维化。在 PDAC 的临床前小鼠模型中，我们观察到 ADAM12 在 CAFs 和肿瘤细胞中的表达，但在健康小鼠胰腺中没有。因此，我们在小鼠 PDAC 中测试了针对 ADAM12 的预防性和治疗性疫苗接种，并观察到肿瘤生长延迟以及 CAFs 和肿瘤结纤维增生的减少。这进一步与血管正常化和减轻肿瘤缺氧有关。ADAM12 疫苗诱导肿瘤内 CD8+ T 细胞的重新分布和针对 ADAM12+ 细胞的细胞毒反应。总之，针对内源性成纤维细胞靶标 ADAM12 的疫苗接种可有效消耗 CAF，减少结纤维增生并延迟小鼠 PDAC 的生长。这些结果为开发基于疫苗接种的免疫疗法来治疗肿瘤结纤维增生提供了原理验证。