Responsiveness of Stromal Fibroblasts to IFN-γ Blocks Tumor Growth via Angiostasis

Lu, Yu; Yang, Wei; Qin, Chuan; Zhang, Lianfeng; Deng, Jingjing; Liu, Shubai; Qin, Zhihai

doi:10.4049/jimmunol.0901073

Cited by 62 publications

(58 citation statements)

References 46 publications

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“…Both cytokines have been shown to promote innate and adaptive antitumor immune responses (10). Moreover, they act directly or indirectly through inflammatory cells on tumor blood vessels (11)(12)(13). Most notably, high-dose TNFα disrupts angiogenic vessels and is used in isolated limb perfusion to treat locally advanced melanoma and soft tissue sarcoma (14).…”

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confidence: 99%

Tumor-targeted TNFα stabilizes tumor vessels and enhances active immunotherapy

Johansson

Hamzah

Payne

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

156

155

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Solid tumors are intrinsically resistant to immune rejection. Abnormal tumor vasculature can act as a barrier for immune cell migration into tumors. We tested whether targeting IFNγ and/or TNFα into pancreatic neuroendocrine tumors can alleviate immune suppression. We found that intratumoral IFNγ causes rapid vessel loss, which does not support anti-tumor immunity. In contrast, low-dose TNFα enhances T-cell infiltration and overall survival, an effect that is exclusively mediated by CD8 + effector cells. Intriguingly, lymphocyte influx does not correlate with increased vessel leakiness. Instead, low-dose TNFα stabilizes the vascular network and improves vessel perfusion. Inflammatory vessel remodeling is, at least in part, mediated by tumor-resident macrophages that are reprogrammed to secrete immune and angiogenic modulators. Moreover, inflammatory vessel remodeling with low-dose TNFα substantially improves antitumor vaccination or adoptive T-cell therapy. Thus, low-dose TNFα promotes both vessel remodeling and antitumor immune responses and acts as a potent adjuvant for active immunotherapy.angiogenesis | vessel normalization | macrophage polarization

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mentioning

confidence: 99%

Tumor-targeted TNFα stabilizes tumor vessels and enhances active immunotherapy

Johansson

Hamzah

Payne

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

156

155

View full text Add to dashboard Cite

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“…TNF-α is important in inhibiting tumor growth in most tumors [65]. IFN-γ is mainly secreted by NK cells, which is relevant for inhibiting tumor growth in non-inflammatory-induced tumors [66]. Consequently, the reduction of cytokines with tumor killing may represent another mechanism by which HLA-G can exert its immunosuppression.…”

Section: Discussionmentioning

confidence: 99%

Human Leukocyte Antigen-G Inhibits the Anti-Tumor Effect of Natural Killer Cells via Immunoglobulin-Like Transcript 2 in Gastric Cancer

Wan

Wang

et al. 2017

Cell Physiol Biochem

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Background/Aims: Human leukocyte antigen-G (HLA-G) plays an important role in inhibiting natural killer (NK) cell function and promoting immune escape. However, the specific mechanism of HLA-G on NK in gastric cancer (GC) remains not well understood. This study investigated the expression of HLA-G in GC and the role of HLA-G-effected NK cells in GC progression. Methods: HLA-G expression in GC tissues obtained from 49 patients with GC was analyzed by immunohistochemistry and western blot. The number of tumor-infiltrating NK cells and the expression of their surface receptors were analyzed by immunohistochemistry and flow cytometry, respectively. The effect of HLA-G on NK cell proliferation was examined by Cell Counting Kit-8 (CCK8) assay. LDH release assay was used to evaluate the effect of HLA-G on the cytotoxic activity of NK cells, and the levels of IFN-γ and TNF-α in the co-cultured supernatant were detected by ELISA. Mice bearing a xenograft tumor model were used to examine the effect of HLA-G on the anti-tumor effect of NK cells. Results: HLA-G positive expression was detected in most of the GC tissues, and was correlated with the adverse prognosis of the disease. The expression of HLA-G was negatively associated with the number of tumor-infiltrating NK cells. Furthermore, GC cell lines with overexpressed HLA-G revealed their ability to inhibit the cell proliferation and cytotoxic activity of NK-92MI cells, and reduce the secretion of IFN-γ and TNF-α through immunoglobulin-like transcript 2 (ILT2). Finally, this in vivo experiment was able to prove that HLA-G can inhibit the anti-tumor effect of NK cells through ILT2. Conclusion: The expression of HLA-G was strongly correlated with the adverse prognosis of GC. The reason may be that it inhibits the proliferation and cytotoxic activity of infiltrating NK cells through ILT2.

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“…However, due to highly species specificity, human unlikely exerts direct effects on murine vascular system, but likely acts on tumor cells to indirectly regulate angiogenesis. It was reported that IFN-γ acted as antiangiogenic cytokine by inhibiting the expression of angiogenic factors, such as VEGF or perlecan, in renal cell carcinoma [36], stromal fibroblasts [37], human cornea [38], and WiDr/HT29 colon carcinoma cells[39], or by inducing the expression of anti-angiogenic factor monokine induced by interferon-gamma (MIG, or CXCL9) in non-small cell lung carcinom [40]. Here we would like to make a hypothesis that IFN-γ may exert antiangiogenic effect in nude mice carrying NPC xenografts by regulating the expression of some angiogenic or antiangiogenic factors in NPC cells.…”

Section: Discussionmentioning

confidence: 99%

Adenovirus-mediated delivery of interferon-γ gene inhibits the growth of nasopharyngeal carcinoma

et al. 2012

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BackgroundInterferon-γ (IFN-γ) is regarded as a potent antitumor agent, but its clinical application is limited by its short half-life and significant side effects. In this paper, we tried to develop IFN-γ gene therapy by a replication defective adenovirus encoding the human IFN-γ (Ad-IFNγ), and evaluate the antitumoral effects of Ad-IFNγ on nasopharyngeal carcinoma (NPC) cell lines in vitro and in xenografts model.MethodsThe mRNA levels of human IFN-γ in Ad-IFNγ-infected NPC cells were detected by reverse transcription-polymerase chain reaction (RT-PCR), and IFN-γ protein concentrations were measured by enzyme-linked immunosorbent assay (ELISA) in the culture supernatants of NPC cells and tumor tissues and bloods of nude mice treated with Ad-IFNγ. The effects of Ad-IFNγ on NPC cell proliferation was determined using MTT assay, cell cycle distribution was determined by flow cytometry analysis for DNA content, and cells apoptosis were analyzed by Annexin V-FITC/7-AAD binding assay and hoechst 33342/PI double staining. The anti-tumor effects and toxicity of Ad-IFNγ were evaluated in BALB/c nude mice carrying NPC xenografts.ResultsThe results demonstrated that Ad-IFNγ efficiently expressed human IFN-γ protein in NPC cell lines in vitro and in vivo. Ad-IFNγ infection resulted in antiproliferative effects on NPC cells by inducing G1 phase arrest and cell apoptosis. Intratumoral administration of Ad-IFNγ significantly inhibited the growth of CNE-2 and C666-1 cell xenografts in nude mice, while no significant toxicity was observed.ConclusionsThese findings indicate IFN-γ gene therapy mediated by replication defective adenoviral vector is likely a promising approach in the treatment of nasopharyngeal carcinoma.

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Responsiveness of Stromal Fibroblasts to IFN-γ Blocks Tumor Growth via Angiostasis

Cited by 62 publications

References 46 publications

Tumor-targeted TNFα stabilizes tumor vessels and enhances active immunotherapy

Tumor-targeted TNFα stabilizes tumor vessels and enhances active immunotherapy

Human Leukocyte Antigen-G Inhibits the Anti-Tumor Effect of Natural Killer Cells via Immunoglobulin-Like Transcript 2 in Gastric Cancer

Adenovirus-mediated delivery of interferon-γ gene inhibits the growth of nasopharyngeal carcinoma

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