Fibrolytic vaccination against ADAM12 reduces desmoplasia in preclinical pancreatic adenocarcinomas.

IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL EMBO Molecular Medicine Pub Date : 2024-10-30 DOI:10.1038/s44321-024-00157-4
Jing Chen, Michal Sobecki, Ewelina Krzywinska, Kevin Thierry, Mélissa Masmoudi, Shunmugam Nagarajan, Zheng Fan, Jingyi He, Irina Ferapontova, Eric Nelius, Frauke Seehusen, Dagmar Gotthardt, Norihiko Takeda, Lukas Sommer, Veronika Sexl, Christian Münz, David DeNardo, Ana Hennino, Christian Stockmann
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Abstract

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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针对 ADAM12 的纤维化疫苗接种可减少临床前胰腺腺癌中的脱落细胞。
胰腺导管腺癌(PDAC)的一个标志性特征是大量瘤内纤维化,即脱落细胞增多症(desmoplasia)。脱模增生的特点是癌相关成纤维细胞(CAFs)的扩张和细胞外基质(ECM)的大量增加。在纤维形成过程中,不同的基因会在成纤维细胞中重新激活,例如崩解金属蛋白酶 ADAM12。先前的研究表明,通过免疫治疗消减 ADAM12+ 细胞可减少各种器官的纤维化。在 PDAC 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却没有发现。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,观察到肿瘤生长延迟、CAFs 减少和肿瘤脱钙化。这还与血管正常化和肿瘤缺氧缓解有关。ADAM12 疫苗能诱导肿瘤内 CD8+ T 细胞重新分布,并诱导针对 ADAM12+ 细胞的细胞毒性反应。总之,针对内源性成纤维细胞靶标 ADAM12 的疫苗接种能有效地消耗 CAFs、减少脱钙并延缓小鼠 PDAC 的生长。这些结果为开发基于疫苗的免疫疗法治疗肿瘤脱钙提供了原理性证明。
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来源期刊
EMBO Molecular Medicine
EMBO Molecular Medicine 医学-医学:研究与实验
CiteScore
17.70
自引率
0.90%
发文量
105
审稿时长
4-8 weeks
期刊介绍: EMBO Molecular Medicine is an open access journal in the field of experimental medicine, dedicated to science at the interface between clinical research and basic life sciences. In addition to human data, we welcome original studies performed in cells and/or animals provided they demonstrate human disease relevance. To enhance and better specify our commitment to precision medicine, we have expanded the scope of EMM and call for contributions in the following fields: Environmental health and medicine, in particular studies in the field of environmental medicine in its functional and mechanistic aspects (exposome studies, toxicology, biomarkers, modeling, and intervention). Clinical studies and case reports - Human clinical studies providing decisive clues how to control a given disease (epidemiological, pathophysiological, therapeutic, and vaccine studies). Case reports supporting hypothesis-driven research on the disease. Biomedical technologies - Studies that present innovative materials, tools, devices, and technologies with direct translational potential and applicability (imaging technologies, drug delivery systems, tissue engineering, and AI)
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