P38 MAPK-inhibited dendritic cells induce superior antitumour immune responses and overcome regulatory T-cell-mediated immunosuppression

Yong Lu, Mingjun Zhang, Siqing Wang, Bangxing Hong, Zhiqiang Wang, Haiyan Li, Yuhuan Zheng, Jing Yang, Richard E. Davis, Jianfei Qian, Jian Hou, Qing Yi

    Research output: Contribution to journalArticlepeer-review

    44 Scopus citations

    Abstract

    Dendritic cell (DC)-based cancer immunotherapy is a promising method, but so far has demonstrated limited clinical benefits. Regulatory T cells (Tregs) represent a major obstacle to cancer immunotherapy approaches. Here we show that inhibiting p38 MAPK during DC differentiation enables DCs to activate tumour-specific effector T cells (Teff), inhibiting the conversion of Treg and compromising Treg inhibitory effects on Teff. Inhibition of p38 MAPK in DCs lowers expression of PPAR 3, activating p50 and upregulating OX40L expression in DCs. OX40L/OX40 interactions between DCs and Teff and/or Treg are critical for priming effective and therapeutic antitumour responses. Similarly, p38 MAPK inhibition also augments the T-cell stimulatory capacity of human monocyte-derived DCs in the presence of Treg. These findings contribute to ongoing efforts to improve DC-based immunotherapy in human cancers.

    Original languageEnglish (US)
    Article number4229
    JournalNature Communications
    Volume5
    DOIs
    StatePublished - Jun 24 2014

    ASJC Scopus subject areas

    • Chemistry(all)
    • Biochemistry, Genetics and Molecular Biology(all)
    • General
    • Physics and Astronomy(all)

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