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肿瘤导致的结缔组织增生能够被表达FAP的基质细胞耗尽而阻断

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发表于 2016-1-9 11:58:56 | 显示全部楼层 |阅读模式
Tumor-Promoting Desmoplasia Is Disrupted by Depleting FAP-Expressing Stromal Cells
Malignant cells drive the generation of a desmoplastic and immunosuppressive tumor microenvironment. Cancer-associated stromal cells (CASC) are a heterogeneous population that provides both negative and positive signals for tumor cell growth and metastasis. Fibroblast activation protein (FAP) is a marker of a major subset of CASCs in virtually all carcinomas. Clinically, FAP expression serves as an independent negative prognostic factor for multiple types of human malignancies. Prior studies established that depletion of FAP(+) cells inhibits tumor growth by augmenting antitumor immunity. However, the potential for immune-independent effects on tumor growth have not been defined. Herein, we demonstrate that FAP(+) CASCs are required for maintenance of the provisional tumor stroma because depletion of these cells, by adoptive transfer of FAP-targeted chimeric antigen receptor (CAR) T cells, reduced extracellular matrix proteins and glycosaminoglycans. Adoptive transfer of FAP-CAR T cells also decreased tumor vascular density and restrained growth of desmoplastic human lung cancer xenografts and syngeneic murine pancreatic cancers in an immune-independent fashion. Adoptive transfer of FAP-CAR T cells also restrained autochthonous pancreatic cancer growth. These data distinguish the function of FAP(+) CASCs from other CASC subsets and provide support for further development of FAP(+) stromal cell-targeted therapies for the treatment of solid tumors.
肿瘤导致的结缔组织增生能够被表达FAP的基质细胞耗尽而阻断
恶性肿瘤能够导致结缔组织的增生以及产生免疫抑制的肿瘤微环境。癌症相关的基质细胞(CASC)是一种不均一的细胞群,它能够提为肿瘤细胞的生长和转移提供消极的和积极的信号。成纤维细胞活化蛋白(FAP)是一种几乎在所有癌症中均有表达的标记物。临床上,FAP的表达是多种人类癌症的一个独立的不良因素。之前的研究证实,耗尽FAP+)细胞会抑制肿瘤的生长,增强抗肿瘤免疫能力。然而,对于肿瘤免疫治疗的作用还没有被完全定义清楚。在这里,我们证实了FAP(+)CASC细胞对于肿瘤间质细胞是必须的,因为通过靶向FAPCAR-T细胞处理,能够减少细胞外基质蛋白和多糖的表达。FAP CAR-T细胞的过继移植也能够减少肿瘤血管密度并且约束人肺癌移植肿瘤组织的生长。过继FAP CAR-T细胞也能抑制自体胰腺癌细胞的生长。这些数据能够从其他CASC集合中区分了FAP+CASC的功能,并且进一步支持了使用靶向FAP+)基质细胞的治疗手段来对抗实体肿瘤的证据。
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