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Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Inactivated Sendai virus particles eradicate tumors by inducing immune responses through blocking regulatory T cells
Masayuki Kurooka1, Yasufumi Kaneda
1Division of Gene Therapy Science, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Abstract:
UV-inactivated, replication-defective Sendai virus particles [hemagglutinating virus of Japan envelope (HVJ-E)] injected into murine colon carcinoma (CT26) tumors growing in syngeneic BALB/c mice eradicated 60% to 80% of the tumors and obviously inhibited the growth of the remainder. Induced adaptive antitumor immune responses were dominant in the tumor eradication process because the effect was abrogated in severe combined immunodeficient mice. Murine and human dendritic cells underwent dose-dependent maturation by HVJ-E in vitro. Profiles of cytokines secreted by dendritic cells after HVJ-E stimulation showed that the amount of interleukin-6 (IL-6) released was comparable to that elicited by live HVJ. Real-time reverse transcription-PCR and immunohistochemistry revealed that HVJ-E induced a remarkable infiltration of dendritic cells and CD4+ and CD8+ T cells into tumors. In addition, CT26-specific CTLs were induced with the evidence of enhanced CD8+ T-cell activation in a CD4+CD25- T cell-dependent manner. On the other hand, conditioned medium from dendritic cells stimulated by HVJ-E rescued CD4+CD25- effector T-cell proliferation from Foxp3+CD4+CD25+ regulatory T cell (Treg)-mediated suppression and IL-6 was presumably dominant for this phenomenon. We also confirmed such rescue in mice treated with HVJ-E in vivo. Moreover, antitumor effect of HVJ-E was significantly reduced by an in vivo blockade of IL-6 signaling. This is the first report to show that HVJ-E alone can eradicate tumors and the mechanism through which it induces antitumor immune responses. Because it can enhance antitumor immunity and simultaneously remove Treg-mediated suppression, HVJ-E shows promise as a novel therapeutic for cancer immunotherapy.
Insights
UV-inactivated Sendai virus particles (HVJ-E) eradicated tumors by inducing adaptive antitumor immunity. This therapy enhances T-cell responses and overcomes regulatory T-cell suppression, showing promise for cancer immunotherapy.
Area of Science:
- Immunology
- Virology
- Cancer Research
Background:
- Cancer immunotherapy aims to harness the immune system to eliminate tumors.
- Viral vectors are explored for their potential to stimulate anti-tumor immune responses.
- Regulatory T cells (Tregs) can suppress anti-tumor immunity, limiting therapeutic efficacy.
Purpose of the Study:
- To investigate the anti-tumor efficacy of UV-inactivated Sendai virus particles (HVJ-E).
- To elucidate the immunological mechanisms underlying HVJ-E-mediated tumor eradication.
- To assess the role of dendritic cells, T cells, and interleukin-6 (IL-6) in HVJ-E's anti-tumor effects.
Main Methods:
- Administration of HVJ-E to CT26 tumor-bearing mice.
- Assessment of tumor growth and eradication rates.
- In vitro maturation of dendritic cells (DCs) and cytokine profiling.
- Analysis of immune cell infiltration (DCs, CD4+, CD8+ T cells) in tumors via RT-PCR and immunohistochemistry.
- Evaluation of T-cell proliferation and suppression assays.
- In vivo blockade of IL-6 signaling.
Main Results:
- HVJ-E eradicated 60-80% of established CT26 tumors and inhibited the growth of remaining tumors.
- Tumor eradication was dependent on adaptive immunity, as evidenced by abrogation in immunodeficient mice.
- HVJ-E induced dose-dependent maturation of murine and human dendritic cells.
- HVJ-E stimulated significant infiltration of DCs, CD4+, and CD8+ T cells into tumors.
- HVJ-E induced CT26-specific cytotoxic T lymphocytes (CTLs) and enhanced CD8+ T-cell activation.
- HVJ-E-conditioned DC medium rescued effector T-cell proliferation from Treg-mediated suppression, with IL-6 playing a dominant role.
- In vivo blockade of IL-6 signaling significantly reduced the anti-tumor effect of HVJ-E.
Conclusions:
- HVJ-E alone demonstrates significant tumor eradication capabilities.
- HVJ-E induces potent anti-tumor immune responses by enhancing T-cell activation and infiltration.
- HVJ-E overcomes Treg-mediated suppression, partly through IL-6, thereby promoting effector T-cell activity.
- HVJ-E represents a promising novel therapeutic agent for cancer immunotherapy due to its ability to boost anti-tumor immunity and counteract immune suppression.
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