Induction of antitumor immunity by transduction of CD40 ligand gene and interferon-γ gene into lung cancer

Noguchi, Masahiro; Imaizumi, Kazuyoshi; Kawabe, Tsutomu; Wakayama, Hisashi; Horio, Yoshitsugu; Sekido, Yoshitaka; Hara, Toru; Hashimoto, Naozumi; Takahashi, Masahide; Shimokata, Kaoru; Hasegawa, Yoshinori

doi:10.1038/sj.cgt.7700320

Cited by 26 publications

(17 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…135 Thus, CD154 transgenic expression on multiple myeloma cells can exert a dual effect of direct growth modulation 50,51,135 as well as stimulating tumor-reactive cytotoxic T lymphocyte activity. 136 In murine syngeneic solid tumor models, ADV-CD154 injected directly into established subcutaneous B16 melanoma, MCA -1 sarcoma, or CT26 colon carcinoma produced sustained tumor regression in the majority of tumor-carrying mice. 95,103,109 Systemic immunosensitization can be demonstrated by virtue of immune rejection of contralaterally implanted, nontransfected tumors.…”

Section: Induction Of Antitumor Immunity By Cd154 -Transfected Cellsmentioning

confidence: 99%

“…Similarly, CD154 gene transfer elicited a tumor-specific cytolytic T lymphocyte response that suppressed the growth of established, weakly immunogenic Lewis lung carcinoma in the presence of IFNg. 136 The CD154 -activated T-cell response can be transferred to naïve recipients to protect against subsequent tumor challenge. 106,136 Preestablished murine K1735 melanoma, CMT93 colon, 109 MB -49 bladder, 105 and rat MCA -RH7777 hepatocellular carcinoma 137 also underwent sustained regression following intratumoral injection of CD154 -transfected cells.…”

Section: Induction Of Antitumor Immunity By Cd154 -Transfected Cellsmentioning

confidence: 99%

See 1 more Smart Citation

Prospects for CD40-directed experimental therapy of human cancer

2002

View full text Add to dashboard Cite

CD40, a member of the tumor necrosis factor receptor ( TNF -R ) family, is a surface receptor best known for its capacity to initiate multifaceted activation signals in normal B cells and dendritic cells ( DCs ). CD40 -related treatment approaches have been considered for the experimental therapy of human leukemias, lymphomas, and multiple myeloma, based on findings that CD40 binding by its natural ligand ( CD40L ), CD154, led to growth modulation of malignant B cells. Recent studies also exploited the selective expression of the CD40 receptor on human epithelial and mesenchymal tumors but not on most normal, nonproliferating epithelial tissues. Ligation of CD40 on human breast, ovarian, cervical, bladder, non small cell lung, and squamous epithelial carcinoma cells was found to produce a direct growth -inhibitory effect through cell cycle blockage and / or apoptotic induction with no overt side effects on their normal counterparts. CD154 treatment also heightened tumor rejection immune responses through DC activation, and by increasing tumor immunogenicity through up -regulation of costimulatory molecule expression and cytokine production of epithelial cancer cells. These immunopotentiating features can produce a ''bystander effect'' through which the CD40 -negative tumor subset is eliminated by activated tumor -reactive cytotoxic T cells. However, the potential risk of systemic inflammation and autoimmune consequences remains a concern for systemic CD154 -based experimental therapy. The promise of CD154 as a tumor therapeutic agent to directly modulate tumor cell growth, and indirectly activate antitumor immune response, may depend on selective and / or restricted CD154 expression within the tumor microenvironment. This may be achieved by inoculating cancer vaccines of autologous cancer cells that have been transduced ex vivo with CD154, as documented by recently clinical trials. This review summarizes recent findings on CD154 recombinant protein -and gene therapy -based tumor treatment approaches, and examines our understanding of the multifaceted molecular mechanisms of CD154 -CD40 interactions.

show abstract

Section: Induction Of Antitumor Immunity By Cd154 -Transfected Cellsmentioning

confidence: 99%

Section: Induction Of Antitumor Immunity By Cd154 -Transfected Cellsmentioning

confidence: 99%

Prospects for CD40-directed experimental therapy of human cancer

2002

View full text Add to dashboard Cite

show abstract

“…Production of a significant amount of IFN-g from Allstimulated spleen cells of the mice that had rejected A11/ CD40L cells suggested the induction of cytotoxic T cells besides natural killer cells. Previous studies also showed that antitumor effects were achieved by the expression of CD40L on tumors [5][6][7][8] and reported that the CD40L molecules could stimulate DCs through the CD40/ CD40L interaction. However, these studies did not directly demonstrate that the activation and the maturation of DCs were caused by the expressed CD40L on tumors.…”

Section: Discussionmentioning

confidence: 99%

“…8 The mechanism of CD40L-mediated antitumor effects was suggested to be because of the activation of DCs and subsequent generation of cytotoxic T cells. [5][6][7][8] Recent studies also showed that adenovirus-mediated transfer of the CD40L gene into DCs produced antitumor effects. 9,10 However, the direct interaction between CD40L-expressed tumors and DCs has not been precisely analyzed.…”

Section: -7mentioning

confidence: 99%

T-cell-dependent antitumor effects produced by CD40 ligand expressed on mouse lung carcinoma cells are linked with the maturation of dendritic cells and secretion of a variety of cytokines

Tada

O-Wang

et al. 2003

Cancer Gene Ther

View full text Add to dashboard Cite

CD40/CD40 ligand (CD40L) interaction plays an essential role in cell-mediated immune responses. We examined whether expression of CD40L in murine lung carcinoma (A11) cells could produce antitumor effects. The proliferation rate in vitro of A11 cells transfected with the murine CD40L gene (A11/CD40L) was not different from that of parent cells; however, half of the immunocompetent mice inoculated with A11/CD40L cells did not form tumors and the growth of A11/CD40L tumors developed in the rest of mice was significantly retarded compared with that of parent tumors. Protective immunity was also induced in the mice that had rejected A11/CD40L cells. In T-cell-defective nude mice, these antitumor effects were not observed. Bone-marrow-derived dendritic cells (DCs), when cultured with A11/CD40L cells, formed clusters with the tumors and showed upregulated CD86 expression. Expression of the interleukin-23 (IL-23) p19, IL-12p35, IL-18, interferon-g (IFN-g) and Mig (monokine induced by IFN-g) genes was induced in the DCs that were cultured with A11/CD40L but not with A11 cells, and P40, the subunit of both IL-12 and IL-23, was secreted from the cocultured DCs. These data directly showed that the expression of CD40L in tumors facilitated the interaction between DCs and the tumors, enhanced the maturation of DCs, induced secretion of cytokines, and consequently produced T-cell-dependent systemic immunity.

show abstract

“…[4][5][6] Thus, recombinant adenovirus (RAd)-mediated delivery of murine CD40L to syngeneic mouse models carrying CD40-negative colorectal, lung or bladder carcinomas results in sustained tumor regression. 7,8 The role of immune cells in this effect has been confirmed by infecting DCs ex vivo with murine RAd-CD40L and inoculating them into the subcutaneous tumors. This approach not only eradicated the primary tumor nodule but also protected against subsequent tumor challenge.…”

Section: Introductionmentioning

confidence: 97%

Adenovirus delivery of human CD40 ligand gene confers direct therapeutic effects on carcinomas

et al. 2009

View full text Add to dashboard Cite

CD40, a tumor necrosis factor receptor family member, is an emerging target for cancer therapy being best appreciated as an important regulator of the anti-tumor immune response. In this study, we report the development of a replication-defective recombinant adenovirus (RAd) vector expressing human CD40 ligand (RAd-hCD40L) and show that sustained engagement of the CD40 pathway in malignant cells results in direct anti-proliferative and pro-apoptotic effects. Thus, transduction of CD40-positive bladder, cervical and ovarian carcinoma cell lines with RAd-hCD40L potently inhibits their proliferation in vitro, whereas CD40-negative lines remain unresponsive. RAd-hCD40L is also found to be superior to recombinant CD40L in inducing carcinoma cell death and in amplifying the cytotoxic effects of the chemotherapeutic agents 5-fluorouracil, cis-platin and mitomycin C. Soluble CD40L is produced by RAd-hCD40L transduced carcinoma cells but unlike other soluble tumor necrosis factor family ligands, it does not interfere with the death-promoting activity of its membrane-bound form. In a mouse xenograft tumor model bearing a human bladder carcinoma, intratumoral delivery of RAd-hCD40L suppresses cancer growth. These findings highlight the potential of exploiting the CD40 pathway in carcinomas using CD40L gene transfer alone or in combination with other modalities for cancer therapy. Our results have also broader implications in understanding the multifaceted anti-tumor activities of the CD40 pathway in carcinomas, which thus offer an attractive option for future clinical application.

show abstract

Induction of antitumor immunity by transduction of CD40 ligand gene and interferon-γ gene into lung cancer

Cited by 26 publications

References 37 publications

Prospects for CD40-directed experimental therapy of human cancer

Prospects for CD40-directed experimental therapy of human cancer

T-cell-dependent antitumor effects produced by CD40 ligand expressed on mouse lung carcinoma cells are linked with the maturation of dendritic cells and secretion of a variety of cytokines

Adenovirus delivery of human CD40 ligand gene confers direct therapeutic effects on carcinomas

Contact Info

Product

Resources

About