Immune properties of recombinant vaccinia virus encoding CD154 (CD40L) are determined by expression of virally encoded CD40L and the presence of CD40L protein in viral particles

Bereta, Michał; Bereta, Joanna; Park, Jonas; Medina, Freddy A.; Kwak, Ho Young; Kaufman, Howard L.

doi:10.1038/sj.cgt.7700762

Cited by 15 publications

(21 citation statements)

References 39 publications

(43 reference statements)

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“…As shown in Figure 1B, when T cells were cultured with uninfected DCs (open bars) there was a modest increase in T cell proliferation. In agreement with previous reports, control rV-LacZ-infected DCs (gray bars) inhibited T cell proliferation (35)(36). In contrast to control vaccinia virus infection, T cells stimulated by rV-4-1BBL-infected DCs exhibited a significant increase in proliferation (P < 0.001; Fig.…”

Section: Characterization Of Rv-4-1bblsupporting

confidence: 81%

“…Thus, the combination of B7.1 and 4-1BBL seemed logical since these molecules signal through distinct pathways and likely promote initial priming and later expansion of antigen exposed T cells. These results are also significant in that the expression of 4-1BBL by vaccinia virus was able to overcome the inhibition of T cell priming observed after infection of DC by control vaccinia virus (35)(36).…”

Section: Discussionsupporting

confidence: 54%

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4-1BB ligand enhances tumor-specific immunity of poxvirus vaccines

Kudo-Saito

Hodge

Kwak

et al. 2006

Vaccine

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Purpose-Recombinant poxvirus vaccines have been explored as tumor vaccines. The immunogenicity of these vaccines can be enhanced by co-expressing costimulatory molecules and tumor-associated antigens. While the B7-CD28 interaction has been most comprehensively investigated, other costimulatory molecules utilize different signaling pathways and might provide further cooperation in T cell priming and survival. 4-1BB (CD137) is a TNF family member and is critical for activation and long-term maintenance of primed T-cells. This study was conducted to determine if a poxvirus expressing the ligand for 4-1BB (4-1BBL) could further improve the immune and therapeutic responses of a previously reported poxvirus vaccine expressing a triad of costimulatory molecules (B7.1, ICAM-1, and LFA-3).Experimental Design-A recombinant vaccinia virus expressing 4-1BBL was generated and characterized in an in vitro infection system. This vaccine was then used alone or in combination with a vaccinia virus expressing CEA, B7.1, ICAM-1, and LFA-3 in CEA-transgenic mice bearing established MC38 tumors. Tumor growth and immune responses against CEA and other tumorassociated antigens were determined. The level of anti-apoptotic proteins in responding T cells was determined by flow cytometry on tetramer selected T cells.Results-The combination of 4-1BBL with B7.1-based poxvirus vaccination resulted in significantly enhanced therapeutic effects against CEA-expressing tumors in a CEA transgenic mouse model. This was associated with an increased level of CEA-specific CD4 + and CD8 + T cell responses, induction of antigen spreading to p53 and gp70, increased accumulation of CEA-specific T cells in the tumor microenvironment, and increased expression of bcl-XL and bcl-2 in CD4 + and CD8 + T cells in vaccinated mice. Conclusion-4-1BBLcooperates with B7 in enhancing anti-tumor and immunologic responses using a recombinant poxvirus vaccine model. The inclusion of costimulatory molecules targeting distinct T cell signaling pathways provides a mechanism for enhancing the therapeutic effectiveness of tumor vaccines.

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Section: Characterization Of Rv-4-1bblsupporting

confidence: 81%

Section: Discussionsupporting

confidence: 54%

4-1BB ligand enhances tumor-specific immunity of poxvirus vaccines

Kudo-Saito

Hodge

Kwak

et al. 2006

Vaccine

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“…Two other reports [6,55] showed that recombinant human soluble CD40L alone only induced IL-12 p40 but failed to induce IL-12 p70 production by DCs since IL-12 p70 secretion is IFN-γ dependent. Another report [22] showed that trimeric recombinant human CD40L enhanced the cell surface expression of CD80, CD83, and CD86 and secretion of TNF-α and IL-12 p40 by DC; however, the expression of DC maturation marker CD83 was not demonstrated in a dose-dependent manner [56,57]. Consistent with the current study, only when CD40L was delivered with different viruses, such as vaccinia virus, adenovirus, and lentivirus-expressed CD40L, could CD40L stimulate DCs to produce IL-12 [56–59].…”

Section: Discussionmentioning

confidence: 99%

“…Another report [22] showed that trimeric recombinant human CD40L enhanced the cell surface expression of CD80, CD83, and CD86 and secretion of TNF-α and IL-12 p40 by DC; however, the expression of DC maturation marker CD83 was not demonstrated in a dose-dependent manner [56,57]. Consistent with the current study, only when CD40L was delivered with different viruses, such as vaccinia virus, adenovirus, and lentivirus-expressed CD40L, could CD40L stimulate DCs to produce IL-12 [56–59]. Virus-induced IFN-γ secretion by monocytes may play an important role in enhancing CD40L-triggered DC maturation.…”

Section: Discussionmentioning

confidence: 99%

Incorporation of CD40 ligand into SHIV virus-like particles (VLP) enhances SHIV-VLP-induced dendritic cell activation and boosts immune responses against HIV

Zhang

et al. 2010

Vaccine

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Engagement of CD40 with CD40L induces dendritic cell (DC) maturation and activation, thereby promoting immune responses. The objective of this study was to investigate whether immunization with chimeric CD40L/SHIV virus-like particles (CD40L/SHIV-VLP) could enhance immune responses to SIV Gag and HIV Env proteins by directly activating DCs. We found that CD83, CD40, and CD86 were significantly up-regulated and significantly increased cytokines production were observed after hCD40L/SHIV-VLP treatment in human CD14+ monocyte-derived DCs as compared to SHIV-VLP treatment. Mice immunized with mCD40L/SHIV-VLP showed more than a two-fold increase in HIV Env-specific IgG antibody production, an increase in SIV Gag and HIV Env-specific IFN-γ and IL-4 producing cells, and an increase in HIV Env-specific cytotoxic activity compared to that in SHIV-VLP immunized mice. Furthermore, multifunctional CD4+ Th1 cells, which simultaneously produce IFN-γ, IL-2 and TNF-α triple cytokines, and CD8+ T-cells, which produce IFN-γ were elevated in the mCD40L/SHIV-VLP immunized group. These data demonstrate that chimeric CD40L/SHIV-VLP potently induce DC activation and enhance the magnitude of both humoral and cellular immune responses to the SIV Gag and HIV Env proteins in the mouse model. Therefore, incorporation of CD40L into VLP may represent a novel strategy to develop effective HIV vaccines.

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“…Results of other investigators with CD40L gene transduction into nonhematologic tumors that do not express CD40 and thus cannot upregulate costimulatory molecules must be explained by the transduction of tumor-infiltrating APCs (31,32). Previous studies showed that tumor B cells activated with CD40L secrete several chemokines that directly enhance the migration of tumor-specific T cells to the tumor site (33,34). The expression of costimulatory molecules on tumor cells may also enhance the retention of effector CD8 T cells at the tumor site (35).…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Vaccination against Murine Lymphoma by Intratumoral Injection of Recombinant Fowlpox Virus Encoding CD40 Ligand

Liu

Guardino²,

Chinsangaram³

et al. 2007

Cancer Research

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The interaction between CD40 ligand (CD40L, CD154) and its receptor CD40 on antigen-presenting cells is essential for the initiation of cell-mediated and humoral immune responses. Malignant B cells also express CD40 and respond to CD40L by enhancing expression of costimulatory molecules. In this study, we investigated the therapeutic antitumor effect of intratumoral administration of recombinant fowlpox virus encoding murine CD40L (rF-mCD40L) in a murine B-cell lymphoma model. BALB/c mice with established s.c. and widely metastatic A20 lymphoma tumors were treated with intratumoral injections of rF-mCD40L together with systemic chemotherapy. This combined chemoimmunotherapy resulted in complete tumor regression and long-term survival of the mice. Some tumor cells in the injected sites expressed the CD40L transgene and had increased expression of the CD80 and CD86 costimulatory molecules. The therapeutic effect was dependent on CD8 but not on CD4 T cells. Moreover, there was a requirement that the recombinant CD40L virus be injected directly into the tumor, as opposed to peritumoral or distant sites. Thus, rF-mCD40L injected directly into the tumor microenvironment enhances the immunogenicity of tumor B cells. The results support future plans for intratumoral injection of rF-mCD40L in patients with lymphoma. [Cancer Res 2007;67(14):7037-44]

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Immune properties of recombinant vaccinia virus encoding CD154 (CD40L) are determined by expression of virally encoded CD40L and the presence of CD40L protein in viral particles

Cited by 15 publications

References 39 publications

4-1BB ligand enhances tumor-specific immunity of poxvirus vaccines

4-1BB ligand enhances tumor-specific immunity of poxvirus vaccines

Incorporation of CD40 ligand into SHIV virus-like particles (VLP) enhances SHIV-VLP-induced dendritic cell activation and boosts immune responses against HIV

Therapeutic Vaccination against Murine Lymphoma by Intratumoral Injection of Recombinant Fowlpox Virus Encoding CD40 Ligand

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