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Induction of NKG2D ligand expression on tumor cells by CD8+ T-cell engagement-mediated activation of nuclear factor-kappa B and p300/CBP-associated factor

Oncogene volume 38, pages 7433–7446 (2019)Cite this article

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Abstract

The ligands for the natural killer group 2 (NKG2D) protein render tumor cells susceptible to NKG2D-dependent immune cell attack. However, cancer cells escape from immune surveillance by downregulating NKG2D ligands. We previously discovered that engagement of activated CD8+ T cells and tumor cells induces NKG2D ligands on tumor cells, but the underlying mechanism remains to be defined. Both in vivo mouse tumor models and in vitro cell assays were performed to study the downstream signaling. Our results supported the notion that, upon engagement with the cognate receptors, CD137 ligand and CD40 initiates activation of nuclear factor-kappa B (NF-κB) signaling in tumor cells even in the absence of CD8+ T cells. Like tumor and CD8+ T cell contact-dependent NKG2D ligand induction, this CD137L/CD40-mediated signaling activation was associated with elevated levels of acetyltransferase P300/CBP-associated factor (PCAF), whereas inhibition of phosphorylated NF-κB abrogated PCAF induction. Although stimulation of CD137L/CD40-mediated signaling is vital, inflammatory cytokines, including interferon gamma (IFNγ) and TNFα, also facilitate NKG2D ligand-induced immune surveillance via both facilitating T-cell chemotaxis and CD137L/CD40 induced NF-κB/PCAF activation. Collectively, our results unveil a novel mechanism of NKG2D ligand upregulation involving reverse signaling of CD40 and CD137L on tumor cells which, along with inflammatory cytokines IFNγ and TNFα, stimulate downstream NF-κB and PCAF activation. Understanding this mechanism may help in development of induced NKG2D ligand-dependent T-cell therapy against cancers.

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Acknowledgements

The following Cancer Center Support Grant core resources were used: Genetically Engineered Mouse Facility and Monoclonal Antibody Core Facility with Cancer Center Support Grant P30 CA016672. The authors would like to thank Ms. Kathryn L Hale from the Department of Scientific Publications for editing the manuscript.

Funding

This study was supported by the National Institutes of Health through grant R01 CA200574.

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  1. Division of Pediatrics, Department of Pediatrics Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Jiemiao Hu, Xueqing Xia, Richard Gorlick & Shulin Li

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Hu, J., Xia, X., Gorlick, R. et al. Induction of NKG2D ligand expression on tumor cells by CD8+ T-cell engagement-mediated activation of nuclear factor-kappa B and p300/CBP-associated factor. Oncogene 38, 7433–7446 (2019). https://doi.org/10.1038/s41388-019-0960-x

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