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A whole-cell tumor vaccine modified to express fibroblast activation protein induces antitumor immunity against both tumor cells and cancer-associated fibroblasts.

ABSTRACT: Cancer-associated fibroblasts (CAFs) are common components of the tumor-suppressive microenvironment, and are a major determinant of the poor outcome of therapeutic vaccination. In this study, we modified tumor cells to express the fibroblast activation protein (FAP), which is highly expressed by CAFs, to potentially improve whole-cell tumor vaccines by targeting both tumor cells and CAFs. Tumor cells were transfected with murine FAP plasmids bearing the cationic lipid DOTAP. Its antitumor effects were investigated in three established tumor models. Vaccination with tumor cells expressing FAP eliminated solid tumors and tumors resulting from hematogenous dissemination. This antitumor immune response was mediated by CD8+ T cells. Additionally, we found that CAFs were significantly reduced within the tumors. Furthermore, this vaccine enhanced the infiltration of CD8+ T lymphocytes, and suppressed the accumulation of immunosuppressive cells in the tumor microenvironment. Our results indicated that the FAP-modified whole-cell tumor vaccine induced strong antitumor immunity against both tumor cells and CAFs and reversed the immunosuppressive effects of tumors by decreasing the recruitment of immunosuppressive cells and enhancing the recruitment of effector T cells. This conclusion may have important implications for the clinical use of genetically modified tumor cells as cancer vaccines.

SUBMITTER: Chen M

PROVIDER: S-EPMC4585784 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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A whole-cell tumor vaccine modified to express fibroblast activation protein induces antitumor immunity against both tumor cells and cancer-associated fibroblasts.

Chen Meihua M Xiang Rong R Wen Yuan Y Xu Guangchao G Wang Chunting C Luo Shuntao S Yin Tao T Wei Xiawei X Shao Bin B Liu Ning N Guo Fuchun F Li Meng M Zhang Shuang S Li Minmin M Ren Kexing K Wang Yongsheng Y Wei Yuquan Y

Scientific reports 20150923

Cancer-associated fibroblasts (CAFs) are common components of the tumor-suppressive microenvironment, and are a major determinant of the poor outcome of therapeutic vaccination. In this study, we modified tumor cells to express the fibroblast activation protein (FAP), which is highly expressed by CAFs, to potentially improve whole-cell tumor vaccines by targeting both tumor cells and CAFs. Tumor cells were transfected with murine FAP plasmids bearing the cationic lipid DOTAP. Its antitumor effec ...[more]

PMID: 26394925

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Project description:Immunomodulatory agents that induce antitumor immunity have great potential for treatment of cancer. We have previously shown that interleukin (IL)-31, a proinflammatory cytokine from the IL-6 family, acts as an antiangiogenic agent. Here, we characterize the immunomodulatory effect of IL-31 in breast cancer. In vivo breast carcinoma models including EMT6 and PyMT cell lines were used to analyze the effect of IL-31 on the composition of various immune cells in the tumor microenvironment using high-throughput flow cytometry. In vitro studies using isolated cytotoxic T cells, CD4+ T cells, myeloid-derived suppressor cells (MDSCs) and macrophages were carried out to study IL-31 immunological activity. The generation of recombinant IL-31 bound to IgG backbone was used to test IL-31 therapeutic activity. The growth rate of IL-31-expressing breast carcinomas is decreased in comparison with control tumors due, in part, to antitumor immunomodulation. Specifically, cytotoxic T cell activity is increased, whereas the levels of CD4+ T cells, MDSCs, and tumor-associated macrophages are decreased in IL-31-expressing tumors. These cellular changes are accompanied by a cytokine profile associated with antitumor immunity. In vitro, IL-31 directly inhibits CD4+ Th0 cell proliferation, and the expression of Th2 canonical factors GATA3 and IL-4. It also promotes CD8+ T cell activation through inhibition of MDSC activity and motility. Clinically, in agreement with the mouse data, alterations in immune cell composition in human breast cancer biopsies were found to correlate with high expression of IL-31 receptor A (IL-31Ra) . Furthermore, high coexpression of IL-31Ra, IL-2 and IL-4 in tumors correlates with increased survival. Lastly, to study the therapeutic potential of IL-31, a recombinant murine IL-31 molecule was fused to IgG via a linker region (IL-31-L-IgG). This IL-31-L-IgG therapy demonstrates antitumor therapeutic activity in a murine breast carcinoma model. Our findings demonstrate that IL-31 induces antitumor immunity, highlighting its potential utility as a therapeutic immunomodulatory agent.

Dataset Information

A whole-cell tumor vaccine modified to express fibroblast activation protein induces antitumor immunity against both tumor cells and cancer-associated fibroblasts.

Publications

A whole-cell tumor vaccine modified to express fibroblast activation protein induces antitumor immunity against both tumor cells and cancer-associated fibroblasts.

Similar Datasets

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