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Meng M.,Kunming Medical University | Meng M.,Yunnan Cell Biology and Clinical Translation Research Center | Wang W.,Kunming Medical University | Wang W.,Yunnan Cell Biology and Clinical Translation Research Center | And 20 more authors.
Tumor Biology | Year: 2016

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. © 2016 International Society of Oncology and BioMarkers (ISOBM)

Wang W.,Kunming Medical University | Wang W.,Yunnan Cell Biology and Clinical Translation Research Center | Li R.,Kunming Medical University | Li R.,Yunnan Cell Biology and Clinical Translation Research Center | And 23 more authors.
Scientific Reports | Year: 2015

Studies have proven that IL-2 and IL-15 showed contrasting roles during CIK cells preparation. By employing microarray, we analyzed miRNA expression profiles of PBMC, CIKIL-2 and CIKIL-15. Advanced bioinformatic analyses were performed to explore the key miRNAs which may regulate cell proliferation and anti-tumor activity of CIK. We identified 261 differentially expressed miRNAs (DEMs) between PBMC and CIKIL-2, and 249 DEMs between PBMC and CIKIL-15. MiR-143-3p/miR-145-5p was miRNA cluster which may positively regulate cell proliferation. In contrast, miR-340-5p/miR-340-3p cluster may negatively regulate cell proliferation via induction apoptosis, which may cause decreased cell proliferation capacity of CIKIL-2. MiRNA-target interaction analysis indicated that 10 co-downregulated miRNAs may synergistically turn on the expression of a pool of tumor cytotoxic genes in CIK cells. The DEMs between CIKIL-2 and CIKIL-15 may contribute to enhanced tumor cytotoxic capacity of CIKIL-2. Importantly, we found that repressed miR-193a-5p may regulate the expressions of inhibitory receptor KLRD1. The results of the validation assay have shown that KLRD1 were upregulated in CIK cells. Our findings have provided new insights into mechanisms of CIK cells production and tumor cytotoxic function, and shed light on their safety for clinical trial.

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