Immunization of stromal cell targeting fibroblast activation protein providing immunotherapy to breast cancer mouse model
Immunization of stromal cell targeting fibroblast activation protein providing immunotherapy to breast cancer mouse model
复制标题
靶向成纤维细胞激活蛋白的基质细胞免疫为乳腺癌小鼠模型提供免疫治疗
DOI：
10.1007/s13277-016-4825-4
复制
发表时间：
2016-08-01
期刊：
影响因子：
--
通讯作者：
Hou, Zongliu
中科院分区：
文献类型：
--
作者：
Meng, Mingyao;Wang, Wenju;Hou, Zongliu
与异种肿瘤细胞不同，肿瘤相关成纤维细胞(CAF)在基因上更稳定，是肿瘤免疫治疗的可靠靶点。成纤维细胞激活蛋白(FAP)在体内的肿瘤细胞和CAF中有限制性表达，在肿瘤的发生、发展和转移中起重要作用，可作为肿瘤排斥反应抗原发挥作用。在本研究中，我们在体内构建了模拟FAP+CAF的人工FAP+基质细胞。我们用FAP+基质细胞免疫乳腺癌小鼠模型，对肿瘤微环境中的FAP+细胞进行免疫治疗。通过强制表达FAP，我们获得了表型为CD11b+/CD34+/Sca-1+/FSP-1+/MHC Class I+的FAP+基质细胞。有趣的是，FAP显著增强了成纤维细胞的增殖能力。在乳腺癌荷瘤小鼠模型中，接种FAP+基质细胞明显抑制了移植瘤的生长，确实减少了肺转移。T细胞耗竭实验表明，CD4+和CD8+T细胞均参与了肿瘤的细胞毒免疫反应。此外，FAP免疫小鼠的肿瘤组织显示，靶向FAP+CAF可诱导肿瘤微环境中的细胞凋亡，并减少I型胶原和CD31的表达。这些结果表明，FAP+基质细胞免疫导致了肿瘤微环境的破坏。我们的研究可能为多种癌症的免疫治疗提供一种新的策略。
Unlike heterogeneous tumor cells, cancer-associated fibroblasts (CAF) are genetically more stable which serve as a reliable target for tumor immunotherapy. Fibroblast activation protein (FAP) which is restrictively expressed in tumor cells and CAF in vivo and plays a prominent role in tumor initiation, progression, and metastasis can function as a tumor rejection antigen. In the current study, we have constructed artificial FAP+stromal cells which mimicked the FAP+CAF in vivo. We immunized a breast cancer mouse model with FAP+stromal cells to perform immunotherapy against FAP+cells in the tumor microenvironment. By forced expression of FAP, we have obtained FAP+stromal cells whose phenotype was CD11b+/CD34+/Sca-1+/FSP-1+/MHC class I+. Interestingly, proliferation capacity of the fibroblasts was significantly enhanced by FAP. In the breast cancer-bearing mouse model, vaccination with FAP+stromal cells has significantly inhibited the growth of allograft tumor and reduced lung metastasis indeed. Depletion of T cell assays has suggested that both CD4+and CD8+T cells were involved in the tumor cytotoxic immune response. Furthermore, tumor tissue from FAP-immunized mice revealed that targeting FAP+CAF has induced apoptosis and decreased collagen type I and CD31 expression in the tumor microenvironment. These results implicated that immunization with FAP+stromal cells led to the disruption of the tumor microenvironment. Our study may provide a novel strategy for immunotherapy of a broad range of cancer.