OX40 ligand expressed by DCs costimulates NKT and CD4+ Th cell antitumor immunity in mice
Jamal Zaini, … , Toshihiro Nukiwa, Toshiaki Kikuchi
Jamal Zaini, … , Toshihiro Nukiwa, Toshiaki Kikuchi
Published November 1, 2007
Citation Information: J Clin Invest. 2007;117(11):3330-3338. https://doi.org/10.1172/JCI32693.
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Research Article

OX40 ligand expressed by DCs costimulates NKT and CD4+ Th cell antitumor immunity in mice

Abstract

The exceptional immunostimulatory capacity of DCs makes them potential targets for investigation of cancer immunotherapeutics. We show here in mice that TNF-α–stimulated DC maturation was accompanied by increased expression of OX40 ligand (OX40L), the lack of which resulted in an inability of mature DCs to generate cellular antitumor immunity. Furthermore, intratumoral administration of DCs modified to express OX40L suppressed tumor growth through the generation of tumor-specific cytolytic T cell responses, which were mediated by CD4+ T cells and NKT cells. In the tumors treated with OX40L-expressing DCs, the NKT cell population significantly increased and exhibited a substantial level of IFN-γ production essential for antitumor immunity. Additional studies evaluating NKT cell activation status, in terms of IFN-γ production and CD69 expression, indicated that NKT cell activation by DCs presenting α-galactosylceramide in the context of CD1d was potentiated by OX40 expression on NKT cells. These results show a critical role for OX40L on DCs, via binding to OX40 on NKT cells and CD4+ T cells, in the induction of antitumor immunity in tumor-bearing mice.

Authors

Jamal Zaini, Sita Andarini, Minoru Tahara, Yasuo Saijo, Naoto Ishii, Kazuyoshi Kawakami, Masaru Taniguchi, Kazuo Sugamura, Toshihiro Nukiwa, Toshiaki Kikuchi

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Figure 2

Tumor-bearing mice treated with intratumoral administration of AdOX40L-modified DCs.

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Tumor-bearing mice treated with intratumoral administration of AdOX40L-m...
(A) Tumor growth. B16-F10 tumor–bearing mice were treated by intratumoral injection of DCs modified with AdOX40L (circles) or AdNull (triangles). Tumor-bearing mice without any treatment (squares) were used as controls. (B) Tumor-specific cytotoxic T cell response. Ten days after the treatment described in A, splenocytes were isolated and then assayed for cytolytic function by using B16-F10 or LLC cells as target cells. (C) Immunohistochemical evaluation of tumors’ CD4+ and CD8+ cells. Three days after the treatment described in A, the tumors were dissected, and the frozen tumor sections were stained with anti-CD4 or anti-CD8 antibodies. Numbers at bottom right of each panel denote the number of positive cells per 10 random high-power fields (original magnification, ×400). (D) Role of CD4+ and CD8+ T cells in tumor growth. The study was similar to that in A, but CD4+ T cell–/– (circles), CD8+ T cell–/– (triangles) or wild-type mice (blue squares) bearing B16-F10 tumors were treated with AdOX40L-modified DCs. (E) Role of CD4+ and CD8+ T cells in tumor-specific cytotoxic T cell response. Ten days after the treatment as in D, splenocytes were isolated and assayed for cytolytic function. (F) Role of OX40 on CD4+ T cells and in tumor growth. The study was similar to that in D, but the CD4+ T cell–/– mice were reconstituted with OX40–/– (circles) or wild-type CD4+ T cells (triangles) 1 day before the treatment.