Anti-tumor effects of DNA vaccine targeting human fibroblast activation protein α by producing specific immune responses and altering tumor microenvironment in the 4T1 murine breast cancer model

Xia, Qi‐Dong; Zhang, Fang-Fang; Geng, Fei; Liu, Chenlu; Xu, Ping; Lu, Zhigang; Yu, Bin; Wu, Hui; Wu, Jiaxin; Zhang, Haihong; Kong, Wei; Yu, Xianghui

doi:10.1007/s00262-016-1827-4

Cited by 43 publications

(34 citation statements)

References 36 publications

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“…Earlier, it was shown that Luc DNA immunization can induce a CTL-mediated resistance to the growth of Luc-expressing tumors 14 . In case of 4T1 tumors, an effective immune response against one of the tumor associated antigens, fibroblast activation protein α overexpressed by cancer-associated fibroblasts, successfully reduced 4T1 tumor growth, also in a CTL-mediated fashion 49 . Our data on unsuccessful Luc DNA-immunization reveals that cancer vaccine candidates can be easily compromised by an inappropriate administration mode.…”

Section: Discussionmentioning

confidence: 99%

Luciferase Expression Allows Bioluminescence Imaging But Imposes Limitations on the Orthotopic Mouse (4T1) Model of Breast Cancer

Baklaushev

Kilpeläinen

Petkov

et al. 2017

Sci Rep

103

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Implantation of reporter-labeled tumor cells in an immunocompetent host involves a risk of their immune elimination. We have studied this effect in a mouse model of breast cancer after the orthotopic implantation of mammary gland adenocarcinoma 4T1 cells genetically labelled with luciferase (Luc). Mice were implanted with 4T1 cells and two derivative Luc-expressing clones 4T1luc2 and 4T1luc2D6 exhibiting equal in vitro growth rates. In vivo, the daughter 4T1luc2 clone exhibited nearly the same, and 4T1luc2D6, a lower growth rate than the parental cells. The metastatic potential of 4T1 variants was assessed by magnetic resonance, bioluminescent imaging, micro-computed tomography, and densitometry which detected 100-μm metastases in multiple organs and bones at the early stage of their development. After 3–4 weeks, 4T1 generated 11.4 ± 2.1, 4T1luc2D6, 4.5 ± 0.6; and 4T1luc2, <1 metastases per mouse, locations restricted to lungs and regional lymph nodes. Mice bearing Luc-expressing tumors developed IFN-γ response to the dominant CTL epitope of Luc. Induced by intradermal DNA-immunization, such response protected mice from the establishment of 4T1luc2-tumors. Our data show that natural or induced cellular response against the reporter restricts growth and metastatic activity of the reporter-labelled tumor cells. Such cells represent a powerful instrument for improving immunization technique for cancer vaccine applications.

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Section: Discussionmentioning

confidence: 99%

Luciferase Expression Allows Bioluminescence Imaging But Imposes Limitations on the Orthotopic Mouse (4T1) Model of Breast Cancer

Baklaushev

Kilpeläinen

Petkov

et al. 2017

Sci Rep

103

View full text Add to dashboard Cite

show abstract

“…The vaccine successfully reduced the growth of 4T1 tumours by producing a specific CTL response to FAPα that killed CAFs. 100 FAPα-based vaccines may be used to induce FAPαspecific CTLs to kill CAFs and destroy immunosuppressive components in the TME. 101,102 These vaccines can also reduce the risk of immune escape, which is an advantage that tumour-associated antigen (TAA) does not have.…”

Section: Anti -C An Cer-a Sso Ciated Fib Rob L a S T Ther Apie Smentioning

confidence: 99%

Crosstalk between cancer‐associated fibroblasts and immune cells in cancer

Liu

Chen

et al. 2019

J Cellular Molecular Medi

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Multiple studies have shown that cancer‐associated fibroblasts (CAFs) play an important role in tumour progression, including carcinogenesis, invasion, metastasis and the chemoresistance of cancer cells. Immune cells, including macrophages, natural killer cells, dendritic cells and T cells, play a dual role in the tumour microenvironment. Although increasing research has focused on studying interactions between distinct cells in the tumour microenvironment, the complex relationships between CAFs and immune cells remain unclear and need further study. Here, we summarize our current understanding of crosstalk between CAFs and immune cells, which may help clarify their diagnostic and therapeutic value in tumour progression.

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“…For example, Alexander et al [44] evaluated the efficacy of an allogeneic cancer cell vaccine enhanced by xenogeneic melanoma antigen in a melanoma model of pet dogs, and the vaccine resulted in an overall response rate of 17% and a cancer control rate of 35%. An early study showed that a DNA vaccine targeting hFAPa suppressed breast cancer growth by eliciting specific cellular immune responses and altering the TME in a mouse model [45]. In the present study, we modified murine tumour cells expressing hFAPa as a WCTV to break the mouse immune tolerance to FAPa.…”

Section: Discussionmentioning

confidence: 96%

Anti-tumour effects of a xenogeneic fibroblast activation protein-based whole cell tumour vaccine in murine tumour models

Chen

Fan

et al. 2019

Artificial Cells, Nanomedicine, and Biotechnology

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The clinical benefit of cancer immunotherapy, including tumour vaccines, is influenced by immunosuppressive factors in the tumour microenvironment. Among these factors, cancer-associated fibroblasts (CAFs) and their products, such as fibroblast activation protein-a (FAPa), greatly affect tumourigenesis, development, metastasis and treatment tolerance, which make them promising immunotherapy targets for cancer patients. Our previous study reported that a whole cell tumour vaccine (WCTV) expressing FAPa inhibited tumour growth by simultaneously attacking cancer cells and CAFs. This study aimed to improve WCTVs with xenoantigens to end immune tolerance and to further activate the adaptive immune system. In the present study, we designed a WCTV by transducing a vector encoding human FAPa (hFAPa) into murine tumour cells and evaluated its efficacy in multiple solid tumour models. Immunotherapy with this WCTV effectively delayed tumour growth and prevented recurrence. The anti-tumour responses were clearly linked to antigen-specific cytotoxic T cells, whereas CD4(þ) T lymphocytes also played a role. Humoural immune responses were activated because the adoptive transfer of immunoglobulins induced abscopal anti-tumour effects, and autoantibodies against FAPa were specifically detected in the sera of immunized mice. Moreover, an increased number of apoptotic tumour cells along with a reduced number of CAFs within the tumours suggest that xenogeneic FAPa-based WCTV has the potential to drive T cell and antibody responses against cancer cells and CAFs. This finding could offer an advanced strategy to treat multiple solid tumours with individualized cancer immunotherapy techniques.

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Anti-tumor effects of DNA vaccine targeting human fibroblast activation protein α by producing specific immune responses and altering tumor microenvironment in the 4T1 murine breast cancer model

Cited by 43 publications

References 36 publications

Luciferase Expression Allows Bioluminescence Imaging But Imposes Limitations on the Orthotopic Mouse (4T1) Model of Breast Cancer

Luciferase Expression Allows Bioluminescence Imaging But Imposes Limitations on the Orthotopic Mouse (4T1) Model of Breast Cancer

Crosstalk between cancer‐associated fibroblasts and immune cells in cancer

Anti-tumour effects of a xenogeneic fibroblast activation protein-based whole cell tumour vaccine in murine tumour models

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