Investigation on the anti-tumor efficacy by expression of GPI-anchored mIL-21 on the surface of B16F10 cells in C57BL/6 mice

Zhao, Fengshu; Dou, Jun; Wang, Jing; Chu, Liu; Tang, Qiulin; Wang, Yongfang; Li, Yating; Cao, Minggang; Hu, Weihua; Hu, Kai; He, Xiang; Gu, Ning

doi:10.1016/j.imbio.2009.02.003

Cited by 18 publications

(25 citation statements)

References 38 publications

(25 reference statements)

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“…Others have shown that gene expression of both GM-CSF and IL-21 can significantly inhibit tumors and activate host immunity including CTL and NK cell activation [11,12]. Previously, we studied recombinant plasmids that expressed both GM-CSF and IL-21 in a mouse model of orthotopic liver cancer by intravenous tail vein injection [13].…”

Section: Introductionmentioning

confidence: 99%

Activation of cellular immunity and marked inhibition of liver cancer in a mouse model following gene therapy and tumor expression of GM-SCF, IL-21, and Rae-1

et al. 2013

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BackgroundCancer is both a systemic and a genetic disease. The pathogenesis of cancer might be related to dampened immunity. Host immunity recognizes nascent malignant cells – a process referred to as immune surveillance. Augmenting immune surveillance and suppressing immune escape are crucial in tumor immunotherapy.MethodsA recombinant plasmid capable of co-expressing granulocyte-macrophage colony- stimulating factor (GM-SCF), interleukin-21 (IL-21), and retinoic acid early transcription factor-1 (Rae-1) was constructed, and its effects determined in a mouse model of subcutaneous liver cancer. Serum specimens were assayed for IL-2 and INF-γ by ELISA. Liver cancer specimens were isolated for Rae-1 expression by RT-PCR and Western blot, and splenocytes were analyzed by flow cytometry.ResultsThe recombinant plasmid inhibited the growth of liver cancer and prolonged survival of tumor-loaded mice. Activation of host immunity might have contributed to this effect by promoting increased numbers and cytotoxicity of natural killer (NK) cells and cytotoxic T lymphocytes (CTL) following expression of GM-SCF, IL-21, and Rae-1. By contrast, the frequency of regulatory T cells was decreased, Consequently, activated CTL and NK cells enhanced their secretion of INF-γ, which promoted cytotoxicity of NK cells and CTL. Moreover, active CTL showed dramatic secretion of IL-2, which stimulates CTL. The recombinant expression plasmid also augmented Rae-1 expression by liver cancer cells. Rae-1 receptor expressing CTL and NK cells removed liver cancer.ConclusionsThe recombinant expression plasmid inhibited liver cancer by a mechanism that involved activation of cell-mediated immunity and Rae-1 in liver cancer.

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Section: Introductionmentioning

confidence: 99%

Activation of cellular immunity and marked inhibition of liver cancer in a mouse model following gene therapy and tumor expression of GM-SCF, IL-21, and Rae-1

et al. 2013

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“…27 In general, these membrane-anchored cytokines, including IL-2, IL-4, IL-12, IL-21, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor-α, retain their biological activity and effectively stimulate immune cells and elicit protective antitumor immunity. [28][29][30][31][32][33] As regards IL-12, the in vivo growth rate of tumors transduced with GPI-anchored IL-12 was significantly delayed and the selected tumor clones expressing GPI-IL-12 were completely eliminated. 30 The antitumor effect of GPI-anchored IL-12 can be further enhanced by coexpression of GPI-anchored IL-2 on the same tumor cells.…”

Section: Introductionmentioning

confidence: 99%

Cancer Immunotherapy Using a Membrane-bound Interleukin-12 With B7-1 Transmembrane and Cytoplasmic Domains

Pan

Chen

et al. 2012

Molecular Therapy

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Interleukin-12 (IL-12) has potent antitumor activity, but its clinical application is limited by severe systemic toxicity, which might be alleviated by the use of membrane-anchored IL-12. In the present study, a new membrane-bound IL-12 containing murine single-chain IL-12 and B7-1 transmembrane and cytoplasmic domains (scIL-12-B7TM) was constructed and its efficacy in cancer treatment examined and its protective antitumor mechanism investigated. Surface expression of scIL-12-B7TM on colon adenocarcinoma cells significantly inhibited the growth of subcutaneous tumors, suppressed lung metastasis, and resulted in local and systemic suppression of unmodified tumors. Intratumoral injection of an adenoviral vector encoding scIL-12-B7TM not only resulted in complete regression of a majority of local tumors, but also significantly suppressed the growth of distant, untreated tumors. Moreover, mice that had been treated with scIL-12-B7TM developed memory responses against subsequent tumor challenge. Immunohistochemical staining and in vivo depletion of lymphocyte subpopulations demonstrated that both CD8(+) T cells and CD4(+) T cells contributed to the antitumor activity of scIL-12-B7TM. Importantly, the potent antitumor activities of scIL-12-B7TM were achieved with only negligible amounts of IL-12 in the circulation. Our data demonstrate that cancer immunotherapy using membrane-bound IL-12 has the advantage of minimizing systemic IL-12 levels without compromising its antitumor efficacy.

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“…However, because of the fact that IL-21 possesses extensive immunomodulating effects, it has recently attracted attention as a tool to generate anti-tumor responses for cancer immunotherapy (di Carlo et al 2007;Sondergaard and Skak 2009;Spolski and Leonard 2008). Several reports demonstrated that administration of recombinant IL-21 (Frederiksen et al 2008;Moroz et al 2004;Sondergaard et al 2010Sondergaard et al , 2007, IL-21 gene expression vectors (Brady et al 2004;Kishida et al 2003;Wang et al 2003), or IL-21 gene-modified cells (Croce et al 2008;Dou et al 2009;Fang et al 2008;Furukawa et al 2006;Kumano et al 2007;Ugai et al 2003a,b;Zhao et al 2010) elicits significant anti-tumor responses. In addition, IL-21 also has the ability to inhibit tumor angiogenesis (Castermans et al 2008).…”

Section: Introductionmentioning

confidence: 99%

Increased expression of IL-21 reduces tumor growth by modulating the status of tumor-infiltrated lymphocytes

et al. 2011

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Investigation on the anti-tumor efficacy by expression of GPI-anchored mIL-21 on the surface of B16F10 cells in C57BL/6 mice

Cited by 18 publications

References 38 publications

Activation of cellular immunity and marked inhibition of liver cancer in a mouse model following gene therapy and tumor expression of GM-SCF, IL-21, and Rae-1

Activation of cellular immunity and marked inhibition of liver cancer in a mouse model following gene therapy and tumor expression of GM-SCF, IL-21, and Rae-1

Cancer Immunotherapy Using a Membrane-bound Interleukin-12 With B7-1 Transmembrane and Cytoplasmic Domains

Increased expression of IL-21 reduces tumor growth by modulating the status of tumor-infiltrated lymphocytes

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