Induction of Efficient Antitumor Immunity Using Dendritic Cells Activated by Recombinant Sendai Virus and Its Modulation by Exogenous <i>IFN</i>-β Gene

Shibata, Satoko; Okano, Shinji; Yonemitsu, Yoshikazu; Onimaru, Manabu; Sata, Shihoko; Nagata-Takeshita, Hiroko; Inoue, Makoto; Zhu, Tsugumine; Hasegawa, Mamoru; Moroi, Yoichi; Furue, Masutaka; Sueishi, Katsuo

doi:10.4049/jimmunol.177.6.3564

Cited by 60 publications

(84 citation statements)

References 37 publications

(47 reference statements)

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“…These tumor extracts were indeed able to block the growth of B16 cells in a type I IFN-dependent manner (Fig. S7), a finding that is consistent with previous reports showing that type I IFNs block proliferation and induce apoptosis of B16 cells (22,23). Together these data indicate that IFN-β is required for the generation of tumor-infiltrating CD8 T cells and for the antitumor activity induced by intratumoral cGAMP.…”

Section: Intratumoral Sting Activation Leads To Systemic Cd8 T-cell-msupporting

confidence: 80%

“…Second, type I IFNs may increase CD8 T-cell infiltration into cGAMP-injected tumors (6) and directly promote their survival and proliferation in the tumor microenvironment (24). However, our data suggest that the potent local antitumor efficacy is not explained by increased CD8 T-cell infiltration of cGAMP-injected tumor but rather by a direct inhibitory effect of type I IFNs on the tumor itself (22,23). Representative plots are given (Upper); each symbol represents an independent mouse (Lower).…”

Section: Discussioncontrasting

confidence: 52%

See 1 more Smart Citation

STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity

Demaria

Gassart

Coso

et al. 2015

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

441

425

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Spontaneous CD8 T-cell responses occur in growing tumors but are usually poorly effective. Understanding the molecular and cellular mechanisms that drive these responses is of major interest as they could be exploited to generate a more efficacious antitumor immunity. As such, stimulator of IFN genes (STING), an adaptor molecule involved in cytosolic DNA sensing, is required for the induction of antitumor CD8 T responses in mouse models of cancer. Here, we find that enforced activation of STING by intratumoral injection of cyclic dinucleotide GMP-AMP (cGAMP), potently enhanced antitumor CD8 T responses leading to growth control of injected and contralateral tumors in mouse models of melanoma and colon cancer. The ability of cGAMP to trigger antitumor immunity was further enhanced by the blockade of both PD1 and CTLA4. The STING-dependent antitumor immunity, either induced spontaneously in growing tumors or induced by intratumoral cGAMP injection was dependent on type I IFNs produced in the tumor microenvironment. In response to cGAMP injection, both in the mouse melanoma model and an ex vivo model of cultured human melanoma explants, the principal source of type I IFN was not dendritic cells, but instead endothelial cells. Similarly, endothelial cells but not dendritic cells were found to be the principal source of spontaneously induced type I IFNs in growing tumors. These data identify an unexpected role of the tumor vasculature in the initiation of CD8 T-cell antitumor immunity and demonstrate that tumor endothelial cells can be targeted for immunotherapy of melanoma.M etastatic melanoma is a highly aggressive cancer with a fast increasing incidence worldwide. Unless diagnosed early and surgically resected, the disease becomes metastatic and life threatening. Both chemotherapy and irradiation are ineffective. Novel therapies that target oncogenic drivers have brought some improvements, but tumor cells escape regularly (1). Melanoma is a prototypical immunogenic tumor, as shown by the occurrence of spontaneous CD8 T-cell responses that drive tumor regressions and by the identification of CD8 T cells that recognize melanoma antigens (2, 3). Although many immunotherapeutic strategies have been developed to induce such responses, clinical efficacies have been poor. More recently, "checkpoint blockade" therapies that target T-cell-inhibitory pathways mediated by CTLA4 (4) and PD1 (5) have yielded encouraging clinical results and demonstrated that spontaneous CD8 T-cell responses in tumors can be boosted to treat melanoma.The mechanisms that drive spontaneous antitumor immune responses are poorly understood. Type I IFNs (IFN-α and IFN-β) may play a role as the expression type I IFN-related genes in primary melanoma has been associated with spontaneous tumor regressions (6) and correlated to the tumor infiltration by specific CD8+ T cells (6, 7). Furthermore, the lack of type I IFN signaling or IFN-β expression inhibited the generation of tumor-specific CD8 T cells and accelerated tumor growth in a murine melanoma mo...

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Section: Intratumoral Sting Activation Leads To Systemic Cd8 T-cell-msupporting

confidence: 80%

Section: Discussioncontrasting

confidence: 52%

STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity

Demaria

Gassart

Coso

et al. 2015

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

441

425

View full text Add to dashboard Cite

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“…This result is presumably due to the low virus titer (5310 7 pfu) administered in the present study; other studies employed a higher virus titer (.1310 9 pfu). 21,34 These results indicate that the administration of BV-DCs did not impair liver and kidney functions in mice.…”

Section: Levels Of Alt Ast and Creatinine Were Not Increased In Bv-dmentioning

confidence: 68%

“…Several groups have reported that regulatory T cells (CD4 1 CD25 1 Foxp3 1 ) are induced by tumor cells and inhibit antitumor immunity, whereas other groups have reported an inhibitory effect of tumor cells that suppresses the host antitumor immune response. [32][33][34] Our data suggest that regulatory T cells may inhibit tumor growth suppression. Previously, we and other groups reported that wild-type baculovirus impairs liver function in mice.…”

Section: Discussionmentioning

confidence: 99%

Induction of antitumor immunity against mouse carcinoma by baculovirus-infected dendritic cells

et al. 2010

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A dendritic cell (DC) vaccine strategy has been developed as a new cancer immunotherapy, but the goal of complete tumor eradication has not yet been achieved. We have previously shown that baculoviruses potently infect DCs and induce antitumor immunity against hepatomas in a mouse model. Baculovirus-infected, bone marrow-derived DCs (BMDCs) display increased surface expression of costimulatory molecules, such as CD80, CD86 and major histocompatibility complex (MHC) classes I and II, and secrete interferons and other proinflammatory cytokines. In this study, we evaluated the induction of antitumor immunity in mice by baculovirus-infected BMDCs against lung cancer and melanoma. After treatment with baculovirus-infected BMDCs, murine lung tumors caused by Lewis lung carcinoma (LLC) cells were significantly reduced in size, and the survival of the mice was improved. In addition, experiments using a melanoma mouse model showed that baculovirus-infected BMDCs inhibited tumor growth and improved survival compared with controls. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and creatinine levels remained normal in baculovirus-infected BMDC-treated mice. Our findings show that baculovirus-infected DCs induce antitumor immunity and pave the way for the use of this technique as an effective tool for DC immunotherapy against malignancies.

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“…Target cells (YAC-1; obtained from the American Type Culture Center, Manassas, VA, USA) were labeled with 100 mCi of Na 2 51 CrO 4 for 1.5 h, and the Cr release assay was performed as described previously. 31 The percentage of specific 51 Cr release or triplicates was calculated as follows: ((experimental counts per minute (c.p.m. )Àspontaneous c.p.m.…”

Section: Nk Cell Activitymentioning

confidence: 99%

Impact of deletion of envelope-related genes of recombinant Sendai viruses on immune responses following pulmonary gene transfer of neonatal mice

et al. 2007

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We demonstrated previously that the additive-type recombinant Sendai virus (rSeV) is highly efficient for use in pulmonary gene transfer; however, rSeV exhibits inflammatory responses. To overcome this problem, we tested newly developed non-transmissible constructs, namely, temperature-sensitive F-deleted vector, rSeV/dF (ts-rSeV/dF) and a rSeV with all the envelope-related genes deleted (rSeV/ dFdMdHN), for pulmonary gene transfer in neonatal mice, by assessing their toxicity and immune responses. The gene expression in the lungs of neonatal ICR mice peaked on day 2, then gradually decreased until almost disappearing at 14 days after infection in all constructs. Loss of body weight and mortality rate, however, were dramatically improved in mice treated with SeV/dFdMdHN (mortality ¼ 0%, n ¼ 41) and ts-rSeV/dF (24.2%, n ¼ 33) compared with additive rSeV (70.7%, n ¼ 58). Although the deletion of envelope-related genes of SeV had a small impact on the production of antibody and cytotoxic T-lymphocyte activity in both adults and neonates, a dramatic reduction was found in the events related to innate responses, including the production of proinflammatory cytokines, particularly in the case of neonates. These results indicate that pulmonary gene transfer using SeV/dFdMdHN warrants further investigation for its possible use in developing safer therapeutics for neonatal lung diseases, including cystic fibrosis.

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Induction of Efficient Antitumor Immunity Using Dendritic Cells Activated by Recombinant Sendai Virus and Its Modulation by Exogenous IFN-β Gene

Cited by 60 publications

References 37 publications

STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity

STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity

Induction of antitumor immunity against mouse carcinoma by baculovirus-infected dendritic cells

Impact of deletion of envelope-related genes of recombinant Sendai viruses on immune responses following pulmonary gene transfer of neonatal mice

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