NQO1 targeting prodrug triggers innate sensing to overcome checkpoint blockade resistance

• Published in: Nature communications Vol. 10; no. 1; pp. 3251 - 13
• Main Authors: Li, Xiaoguang, Liu, Zhida, Zhang, Anli, Han, Chuanhui, Shen, Aijun, Jiang, Lingxiang, Boothman, David A., Qiao, Jian, Wang, Yang, Huang, Xiumei, Fu, Yang-Xin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.07.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/21; 13/31; 14/1; 14/19; 38/77; 42/109; 631/250; 64/60; 692/4028/67; 82/80; A549 Cells; Adaptive immunity; Animals; Antigen presentation; Cell activation; Cell Line, Tumor; Dendritic cells; Detection; HMGB1 protein; Humanities and Social Sciences; Humans; Immune checkpoint; Immunity, Innate - drug effects; Immunity, Innate - immunology; Immunotherapy; Interferon; Lapachone; Lymphocytes; Lymphocytes T; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; multidisciplinary; MyD88 protein; NAD; NAD(P)H Dehydrogenase (Quinone) - antagonists & inhibitors; NAD(P)H Dehydrogenase (Quinone) - genetics; NAD(P)H Dehydrogenase (Quinone) - metabolism; NADPH quinone oxidoreductase; Naphthoquinones - pharmacology; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - immunology; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - genetics; Neoplasms, Experimental - metabolism; Oxidative stress; Priming; Prodrugs - pharmacology; Quinone oxidoreductase; Quinones; Reactive Oxygen Species - metabolism; Science; Science (multidisciplinary); Signal Transduction - drug effects; Signal Transduction - genetics; Signal Transduction - immunology; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; TLR4 protein; Toll-like receptors; Tumor cells; Tumors; Xenograft Model Antitumor Assays
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-11238-1

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 NQO1 high 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. Improper innate sensing within the tumor microenvironment limits immunotherapy success. Here, the authors show that targeting NQO1 triggers immunogenic innate sensing to reactivate T cells and overcome immune checkpoint blockade resistance.