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 () and Qing Yi ()
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Yong Lu: Lerner Research Institute, Cleveland Clinic
Mingjun Zhang: Lerner Research Institute, Cleveland Clinic
Siqing Wang: Institute of Translational Medicine, The First Hospital, Jilin University
Bangxing Hong: Lerner Research Institute, Cleveland Clinic
Zhiqiang Wang: The University of Texas MD Anderson Cancer Center
Haiyan Li: Lerner Research Institute, Cleveland Clinic
Yuhuan Zheng: Lerner Research Institute, Cleveland Clinic
Jing Yang: The University of Texas MD Anderson Cancer Center
Richard E. Davis: The University of Texas MD Anderson Cancer Center
Jianfei Qian: Lerner Research Institute, Cleveland Clinic
Jian Hou: Chang Zheng Hospital, The Second Military University
Qing Yi: Lerner Research Institute, Cleveland Clinic

Nature Communications, 2014, vol. 5, issue 1, 1-14

Abstract: 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 PPARγ, 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.

Date: 2014
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DOI: 10.1038/ncomms5229

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