Ablation of Cbl-b provides protection against transplanted and spontaneous tumors
Jeffrey Y. Chiang, … , Richard Hodes, Hua Gu
Jeffrey Y. Chiang, … , Richard Hodes, Hua Gu
Published April 2, 2007
Citation Information: J Clin Invest. 2007;117(4):1029-1036. https://doi.org/10.1172/JCI29472.
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Ablation of Cbl-b provides protection against transplanted and spontaneous tumors

Abstract

A significant challenge to efforts aimed at inducing effective antitumor immune responses is that CD8+ T cells, which play a prominent role in these responses, may be unable to respond to tumors that lack costimulatory signals and that are protected by an immune suppressive environment such as that mediated by TGF-β produced by tumor cells themselves or by infiltrating Tregs, often resulting in tolerance or anergy of tumor-specific T cells. Here we show that the in vitro activation of Cblb–/– CD8+ T cells does not depend on CD28 costimulation and is resistant to TGF-β suppression. In vivo studies further demonstrated that Cblb–/– mice, but not WT controls, efficiently rejected inoculated E.G7 and EL4 lymphomas that did not express B7 ligands and that introduction of the Cblb–/– mutation into tumor-prone ataxia telangiectasia mutated–deficient mice markedly reduced the incidence of spontaneous thymic lymphomas. Immunohistological study showed that E.G7 tumors from Cblb–/– mice contained massively infiltrating CD8+ T cells. Adoptive transfer of purified Cblb–/– CD8+ T cells into E.G7 tumor-bearing mice led to efficient eradication of established tumors. Thus, our data indicate that ablation of Cbl-b can be an efficient strategy for eliciting immune responses against both inoculated and spontaneous tumors.

Authors

Jeffrey Y. Chiang, Ihn Kyung Jang, Richard Hodes, Hua Gu

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Figure 1

CD28-independent proliferation and cytokine production by Cblb–/– CD8+ T cells.

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CD28-independent proliferation and cytokine production by Cblb–/– CD8+ T...
(A) IL-2 and IFN-γ production. Purified CD8+ T cells from WT and Cblb–/– mice were stimulated with either plate-bound anti-CD3 or plate-bound anti-CD3 plus soluble anti-CD28 antibodies. IL-2– and IFN-γ–producing cells were visualized by intracellular staining and analyzed by flow cytometry. Shown are contour plots of intracellular staining for IL-2 and IFN-γ expression in CD8+ T cells. Percentages of IL-2– and IFN-γ–producing cells are indicated in the plots as mean ± SD from 3 independent experiments. The boxed regions indicate the gates used for calculation of the percentage of CD8+ T cells staining positive for IFN-γ. (B) TCR-induced proliferative response. Purified CD8+ T cells from WT and Cblb–/– mouse lymph nodes and spleens were stimulated with various concentrations of anti-CD3 antibodies in the presence or absence of anti-CD28 antibodies. Cell proliferation was determined by [3H]-thymidine incorporation and presented as mean ± SD for triplicate samples. Shown are representatives of 3 independent experiments. (C) Resistance of Cblb–/– CD8+ T cells to TGF-β suppression. Histograms (left) show CSFE intensities of labeled Cblb–/– and WT CD8+ T cells after 3 days of anti-CD3 and anti-CD28 stimulation. Cells were cultured in the absence or presence of different concentrations of TGF-β as indicated in the figure. Contour plots (bottom) show the IFN-γ production in the absence or presence of TGF-β. Percentages of IFN-γ+ cells are indicated in the plots.