Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake
Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake
复制标题
DOI：
10.1172/jci26532
复制
发表时间：
2006-07-01
影响因子：
15.9
通讯作者：
Reisfeld, Ralph A.
中科院分区：
文献类型：
--
作者：
Loeffler, Markus;Krueger, Joerg A.;Reisfeld, Ralph A.
肿瘤相关成纤维细胞是肿瘤发生的关键调节因子。与遗传不稳定且频繁突变的肿瘤细胞相反，肿瘤间质隔室中遗传更稳定的成纤维细胞的存在使其成为癌症免疫治疗的最佳靶点。这些细胞也是1型胶原蛋白的主要来源，1型胶原蛋白有助于降低肿瘤中的化疗药物摄取，并在调节肿瘤对各种化疗的敏感性方面发挥重要作用。为了特异性杀死肿瘤相关的成纤维细胞，我们构建了一种靶向成纤维细胞活化蛋白（FAP）的口服DNA疫苗，该蛋白在肿瘤基质中由成纤维细胞特异性过表达。通过CD8（+）T细胞介导的肿瘤相关成纤维细胞的杀伤，我们的疫苗成功地抑制了多药耐药小鼠结肠癌和乳腺癌的原发肿瘤细胞生长和转移。此外，FAP疫苗接种小鼠的肿瘤组织显示I型胶原蛋白表达显著降低，化疗药物的摄取增加高达70%。最重要的是，用化疗处理的pFap疫苗接种的小鼠显示出3倍的寿命延长和显著的肿瘤生长抑制，50%的动物完全拒绝肿瘤细胞攻击。这一策略为免疫和化疗的结合开辟了新的途径。
Tumor-associated fibroblasts are key regulators of tumorigenesis. In contrast to tumor cells, which are genetically unstable and mutate frequently, the presence of genetically more stable fibroblasts in the tumor-stromal compartment makes them an optimal target for cancer immunotherapy. These cells are also the primary source of collagen type 1, which contributes to decreased chemotherapeutic drug uptake in tumors and plays a significant role in regulating tumor sensitivity to a variety of chemotherapies. To specifically kill tumor-associated fibroblasts, we constructed an oral DNA vaccine targeting fibroblast activation protein (FAP), which is specifically overexpressed by fibroblasts in the tumor stroma. Through CD8(+) T cell-mediated killing of tumor-associated fibroblasts, our vaccine successfully suppressed primary tumor cell growth and metastasis of multidrug-resistant murine colon and breast carcinoma. Furthermore, tumor tissue of FAP-vaccinated mice revealed markedly decreased collagen type I expression and up to 70% greater uptake of chemotherapeutic drugs. Most importantly, pFap-vaccinated mice treated with chemotherapy showed a 3-fold prolongation in lifespan and marked suppression of tumor growth, with 50% of the animals completely rejecting a tumor cell challenge. This strategy opens a new venue for the combination of immuno- and chemotherapies.