Eliciting protective immune responses against murine myeloma challenge in lymphopenia mice through adoptive transfer of tumor antigen-specific lymphocytes and immunization of tumor vaccine secreting mIL-21

BackgroundGenetically modified cells have been shown to be one of the most effective tumor vaccine strategies. However, in many cases, such as in melanoma, induction of a potent immune responses against the disease still remains a major challenge. Thus, novel strategies to reinforce tumor vaccine efficacy are needed. Using microRNA (miR) and Zinc-finger E-box binding homeobox (ZEB) have received much attention for potentially regulating tumor progression. To elicit a potent antitumor efficacy against melanoma, we used tumor vaccine in combination with miR200c overexpression or ZEB1 knockdown to assess the efficacy of treatment of murine melanoma.MethodsB16F10 cell vaccine expressing interleukin 21 (IL-21) in the glycosylpho- sphatidylinositol (GPI)-anchored form (B16F10/GPI-IL-21) were developed. The vaccine was immunized into mice challenged by B16F10 cells or B16F10 cells stably transduced with lentiviral-miR200c (B16F10/miR200c) or transfected with the ZEB1-shRNA recombinant (B16F10/shZEB1) or the B16F10/GPI-IL-21 vaccine. The immune responses, tumorigenicity and lung metastasis in mice were evaluated, respectively.ResultsThe vaccination with B16F10/GPI-IL-21 markedly increased the serum cytokine levels of IFN-γ, TNF-α, IL-4 and decreased TGF-β level as well as augmented the cytotoxicity of splenocytes in immunized mice compared with control mice. In addition, the tumor vaccine B16F10/GPI-IL-21 significantly inhibited the tumor growth and reduced counts of lung metastases in mice challenged by B16F10/GPI-IL-21, B16F10/shZEB1 and B16F10/miR200c respectively compared with the control mice challenged by B16F10 cells. The efficacy mechanisms may involve in reinforcing immune responses, increasing expression of miR200c, E-cadherin and SMAD-7 and decreasing expression of TGF-β, ZEB1, Vimentin and N-cadherin in tumor tissues from the immunized mice.ConclusionsThese results indicate that the tumor vaccine B16F10/GPI-IL-21 in combination with miR200c overexpression or ZEB1 knockdown effectively inhibited melanoma growth and metastasis a murine model. Such a strategy may, therefore, be used for the clinical trials.

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“…The Kit is suitable for detection of samples including cell culture supernatant and serum, and the sensitivity of Kit is 5.3 pg/mL [23,24]. …”

Section: Methodsmentioning

confidence: 99%

Regulation gene expression of miR200c and ZEB1 positively enhances effect of tumor vaccine B16F10/GPI-IL-21 on inhibition of melanoma growth and metastasis

Wang

Zhao

et al. 2014

J Transl Med

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“…In particular, the mice that received the B16F10/GPI-IL-21 vaccination combined with the B16F10/shTGF-β1 challenge and the administration of miR200c agomir showed stronger CTL and NK activities and lower CD4 + CD25 + Treg cells than any other mice; these treated mice also showed a reduction in the serum TGF-β1 level and an increase in the IFN-γ level. It has been reported that IFN-γ can react to NK cells and CTL, enhance their cytotoxic activities, and play a key biological role in killing tumor cells or inducing tumor cell apoptosis [ 19 - 21 ]. Malignant melanomas secrete high amounts of TGF-β, and the increased circulating plasma concentration is associated with the advanced stage of the tumor.…”

Section: Discussionmentioning

confidence: 99%

Combining TGF-β1 knockdown and miR200c administration to optimize antitumor efficacy of B16F10/GPI-IL-21 vaccine

Wang

Zhao

et al. 2015

Oncotarget

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TGF-β1 secreted abundantly by tumors cells as well as present in the local microenvironment promotes neoplasm invasion and metastasis by triggering the epithelial to mesenchymal transition (EMT). MiR200c has been shown to suppress EMT and to regulate the cellular epithelial and interstitial state conversion, whereas the tumor vaccines are intended to specifically initiate or amplify a host response against evolving tumor cells. Our study aimed at optimizing the antitumor effects of the B16F10/glycosylphosphatidylinositol-interleukin 21 (B16F10/GPI-IL-21) tumor vaccine on melanoma bearing mice by combining the TGF-β1 knockdown and the administration of miR200c agomir. The mice were subcutaneously vaccinated with inactivated B16F10/GPI-IL-21 vaccine and challenged by B16F10 cells transfected with shTGF-β1 (B16F10/shTGF-β1 cells) or B16F10/shTGF-β1 cells with the administration of miR200c agomir. The later combination showed that, when compared with the mice in the control group that received no vaccination, vaccinated mice significantly increased NK and CTL activities, enhanced levels of IFN-γ, and reduced expression of TGF-β1, N-cadherin, Vimentin, Gli1/2, P-Smad2/3 and others involved in promoting expression of EMT-related molecules in tumor areas, and inhibited the melanoma metastasis in lungs and lymph nodes. Altogether, our findings demonstrate that this synergistic anti-cancer regimen effectively induces strong immune response and diminishes the melanoma progression.

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“…A murine IL-21-secreting whole myeloma cell vaccine (mIL-21-Sp2/0) has also been used to prime immune responses against myeloma in vivo. Lymphocytes from mIL-21-Sp2/0-immunized mice infused in mice lymphodepleted by cyclophosphamide treatment induced protective immunity against murine myeloma [ 106 ]. Besides tumor cells, also other cell types transduced with IL-21 gene proved to be effective at inducing antitumor responses.…”

Section: Preclinical Studies Of Il-21 Cancer Immunotherapymentioning

confidence: 99%

IL-21: A Pleiotropic Cytokine with Potential Applications in Oncology

Croce

Rigo

Ferrini

2015

Journal of Immunology Research

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Interleukin- (IL-) 21 is a pleiotropic cytokine that regulates the activity of both innate and specific immunity. Indeed, it costimulates T and natural killer (NK) cell proliferation and function and regulates B cell survival and differentiation and the function of dendritic cells. In addition, IL-21 exerts divergent effects on different lymphoid cell leukemia and lymphomas, as it may support cell proliferation or on the contrary induce growth arrest or apoptosis of the neoplastic lymphoid cells. Several preclinical studies showed that IL-21 has antitumor activity in different tumor models, through mechanism involving the activation of NK and T or B cell responses. Moreover, IL-21's antitumor activity can be potentiated by its combination with other immune-enhancing molecules, monoclonal antibodies recognizing tumor antigens, chemotherapy, or molecular targeted agents. Clinical phase I-II studies of IL-21 in cancer patients showed immune stimulatory properties, acceptable toxicity profile, and antitumor effects in a fraction of patients. In view of its tolerability, IL-21 is also suitable for combinational therapeutic regimens with other agents. This review will summarize the biological functions of IL-21, and address its role in lymphoid malignancies and preclinical and clinical studies of cancer immunotherapy.

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Eliciting protective immune responses against murine myeloma challenge in lymphopenia mice through adoptive transfer of tumor antigen-specific lymphocytes and immunization of tumor vaccine secreting mIL-21

Cited by 8 publications

References 35 publications

Regulation gene expression of miR200c and ZEB1 positively enhances effect of tumor vaccine B16F10/GPI-IL-21 on inhibition of melanoma growth and metastasis

Regulation gene expression of miR200c and ZEB1 positively enhances effect of tumor vaccine B16F10/GPI-IL-21 on inhibition of melanoma growth and metastasis

Combining TGF-β1 knockdown and miR200c administration to optimize antitumor efficacy of B16F10/GPI-IL-21 vaccine

IL-21: A Pleiotropic Cytokine with Potential Applications in Oncology

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