A Whole Cell Tumor Vaccine Expressing Human Fibroblast Activation Protein α Targets Cancer 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.

Download Full-text

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

Scientific Reports ◽

10.1038/srep46841 ◽

2017 ◽

Vol 7 (1) ◽

Author(s):

Meihua Chen ◽

Rong Xiang ◽

Yuan Wen ◽

Guangchao Xu ◽

Chunting Wang ◽

...

Keyword(s):

Tumor Cells ◽

Antitumor Immunity ◽

Tumor Vaccine ◽

Fibroblast Activation Protein ◽

Cell Tumor ◽

Cancer Associated Fibroblasts ◽

Whole Cell ◽

Fibroblast Activation

Download Full-text

Synergistic Effect Of Stereotactic Ablative Radiotherapy And Immunotherapy With A Xenogeneic Fibroblast Activation Protein-Based Whole Cell Tumor Vaccine

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/j.ijrobp.2020.07.1657 ◽

2020 ◽

Vol 108 (3) ◽

pp. e529-e530

Author(s):

M.H. Chen ◽

J. Lang

Keyword(s):

Synergistic Effect ◽

Tumor Vaccine ◽

Fibroblast Activation Protein ◽

Cell Tumor ◽

Stereotactic Ablative Radiotherapy ◽

Whole Cell ◽

Fibroblast Activation

Download Full-text

An improved production and purification protocol for recombinant soluble human fibroblast activation protein alpha

Protein Expression and Purification ◽

10.1016/j.pep.2021.105833 ◽

2021 ◽

Vol 181 ◽

pp. 105833

Author(s):

Cecy R. Xi ◽

Arianna Di Fazio ◽

Naveed Ahmed Nadvi ◽

Michelle Sui Wen Xiang ◽

Hui Emma Zhang ◽

...

Keyword(s):

Human Fibroblast ◽

Fibroblast Activation Protein ◽

Fibroblast Activation ◽

Fibroblast Activation Protein Alpha ◽

Purification Protocol

Download Full-text

Fibroblast activation protein targeted near infrared photoimmunotherapy (NIR PIT) overcomes therapeutic resistance in human esophageal cancer

Scientific Reports ◽

10.1038/s41598-021-81465-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ryoichi Katsube ◽

Kazuhiro Noma ◽

Toshiaki Ohara ◽

Noriyuki Nishiwaki ◽

Teruki Kobayashi ◽

...

Keyword(s):

Esophageal Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Near Infrared ◽

Fibroblast Activation Protein ◽

Therapeutic Resistance ◽

Fibroblast Activation ◽

Human Esophageal Cancer

AbstractCancer-associated fibroblasts (CAFs) have an important role in the tumor microenvironment. CAFs have the multifunctionality which strongly support cancer progression and the acquisition of therapeutic resistance by cancer cells. Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer treatment that uses a highly selective monoclonal antibody (mAb)-photosensitizer conjugate. We developed fibroblast activation protein (FAP)-targeted NIR-PIT, in which IR700 was conjugated to a FAP-specific antibody to target CAFs (CAFs-targeted NIR-PIT: CAFs-PIT). Thus, we hypothesized that the control of CAFs could overcome the resistance to conventional chemotherapy in esophageal cancer (EC). In this study, we evaluated whether EC cell acquisition of stronger malignant characteristics and refractoriness to chemoradiotherapy are mediated by CAFs. Next, we assessed whether the resistance could be rescued by eliminating CAF stimulation by CAFs-PIT in vitro and in vivo. Cancer cells acquired chemoradiotherapy resistance via CAF stimulation in vitro and 5-fluorouracil (FU) resistance in CAF-coinoculated tumor models in vivo. CAF stimulation promoted the migration/invasion of cancer cells and a stem-like phenotype in vitro, which were rescued by elimination of CAF stimulation. CAFs-PIT had a highly selective effect on CAFs in vitro. Finally, CAF elimination by CAFs-PIT in vivo demonstrated that the combination of 5-FU and NIR-PIT succeeded in producing 70.9% tumor reduction, while 5-FU alone achieved only 13.3% reduction, suggesting the recovery of 5-FU sensitivity in CAF-rich tumors. In conclusion, CAFs-PIT could overcome therapeutic resistance via CAF elimination. The combined use of novel targeted CAFs-PIT with conventional anticancer treatments can be expected to provide a more effective and sensible treatment strategy.

Download Full-text

P11.41 Comparison of fibroblast activation protein expression and localization in glioblastomas and brain metastases

Neuro-Oncology ◽

10.1093/neuonc/noz126.187 ◽

2019 ◽

Vol 21 (Supplement_3) ◽

pp. iii52-iii52

Author(s):

P Busek ◽

M Zubal ◽

B Chmielova ◽

Z Vanickova ◽

P Hrabal ◽

...

Keyword(s):

Tumor Microenvironment ◽

Brain Metastases ◽

Cancer Cells ◽

Brain Tissue ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Glioma Cells ◽

Fibroblast Activation Protein ◽

Epithelial Cancer ◽

Fibroblast Activation

Abstract BACKGROUND Fibroblast activation protein (FAP) is a transmembrane serine protease that is frequently upregulated in the tumor microenvironment. In several cases, FAP protein itself and/or FAP expressing stromal cells have been shown to contribute to cancer progression and to be associated with more aggressive cancer behaviour and shorter patient survival. The aim of this study was to determine FAP expression in glioblastomas and brain metastases and to identify the cell types that express FAP in the microenvironment of these malignancies. MATERIAL AND METHODS FAP enzymatic activity and protein concentration were determined in samples from patients with brain metastases, glioblastomas and pharmacoresistant epilepsy (control non-tumorous brain tissue) by an enzymatic assay using a specific fluorogenic substrate and ELISA, respectively. Immunohistochemical labelling with antibodies against FAP and markers of astroglia, epithelial cancer cells and mesenchymal stromal cells was performed to characterize FAP expressing cells. RESULTS FAP was significantly upregulated in the majority of glioblastomas and brain metastases in comparison to non-tumorous brain tissue. In glioblastomas, FAP was localized perivascularly and in mesenchymal cells, and in part of the tumors also in the glioma cells. In brain metastases, FAP positivity was abundantly present in the stroma and predominantly co-localised with markers of mesenchymal stromal cells (TE-7, SMA, PDGFRbeta, NG2), but there was no overlap between FAP and markers of epithelial cancer cells (EpCAM, pancytokeratin). CONCLUSION FAP is upregulated in the microenvironment of human glioblastomas and brain metastases compared to non-tumorous brain tissue. In glioblastomas, FAP is expressed in part of the glioma cells, in pericytes and mesenchymal stromal cells, whereas no positivity in cancer cells and more abundant FAP+ stroma was detected in brain metastases. The selective expression of FAP in these brain tumors may be useful for the visualization and possibly therapeutic targeting of their tumor microenvironment. GRANT SUPPORT Ministry of Health of the Czech Republic, grant No. 15-31379A, Progres Q28/LF1, 2015064 LM EATRIS and the project,Center for Tumor Ecology - Research of the Cancer Microenvironment Supporting Cancer Growth and Spread” (reg. n. CZ.02.1.01/0.0/0.0/16_019/0000785) supported by the Operational Programme Research, Development and Education.

Download Full-text