NQO1 targeting prodrug triggers innate sensing to overcome checkpoint blockade resistance

Xiaoguang Li, Zhida Liu, Anli Zhang, Chuanhui Han, Aijun Shen, Lingxiang Jiang, David A. Boothman, Jian Qiao, Yang Wang, Xiumei Huang () and Yang-Xin Fu ()
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Xiaoguang Li: University of Texas Southwestern Medical Center
Zhida Liu: University of Texas Southwestern Medical Center
Anli Zhang: University of Texas Southwestern Medical Center
Chuanhui Han: University of Texas Southwestern Medical Center
Aijun Shen: University of Texas Southwestern Medical Center
Lingxiang Jiang: Indiana University School of Medicine
David A. Boothman: Indiana University School of Medicine
Jian Qiao: University of Texas Southwestern Medical Center
Yang Wang: University of Texas Southwestern Medical Center
Xiumei Huang: Indiana University School of Medicine
Yang-Xin Fu: University of Texas Southwestern Medical Center

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract Lack of proper innate sensing inside tumor microenvironment (TME) limits T cell-targeted immunotherapy. NAD(P)H:quinone oxidoreductase 1 (NQO1) is highly enriched in multiple tumor types and has emerged as a promising target for direct tumor-killing. Here, we demonstrate that NQO1-targeting prodrug β-lapachone triggers tumor-selective innate sensing leading to T cell-dependent tumor control. β-Lapachone is catalyzed and bioactivated by NQO1 to generate ROS in NQO1high tumor cells triggering oxidative stress and release of the damage signals for innate sensing. β-Lapachone-induced high mobility group box 1 (HMGB1) release activates the host TLR4/MyD88/type I interferon pathway and Batf3 dendritic cell-dependent cross-priming to bridge innate and adaptive immune responses against the tumor. Furthermore, targeting NQO1 is very potent to trigger innate sensing for T cell re-activation to overcome checkpoint blockade resistance in well-established tumors. Our study reveals that targeting NQO1 potently triggers innate sensing within TME that synergizes with immunotherapy to overcome adaptive resistance.

Date: 2019
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DOI: 10.1038/s41467-019-11238-1

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