Abstract 1657: Tumor selective immunotherapy to overcome checkpoint blockade resistance

Abstract Most patients are resistant to PD-1/PD-L1 blockade therapy but mechanisms are not well defined. Defective innate sensing limits reactivation of T cells after the blockade. Patients with well-established solid tumors often generate complicated immunosuppressive networks and are generally refractory to immunotherapy. NAD(P)H:quinone oxidoreductase 1 (NQO1) is a two-electron oxidoreductase elevated (more than 100-fold) in most solid cancers and has emerged as a promising target for direct tumor-killing. Here, we demonstrate that novel NQO1 targeting drug-Isobutyldeoxynyboquinone (IB-DNQ) causes tumor-selective innate sensing leading to T cell dependent tumor suppression. IB-DNQ treatment increases PD-L1 expression in the tumor microenvironment. Upregulated PD-L1 within TME contributes to tumor relapse and provides therapeutic window for combination therapy of IB-DNQ with immune checkpoint blockade. We demonstrate that IB-DNQ or PD-1 blockade treatment alone leads to tumor rejection in mice bearing small but not large established tumors. However, combination therapy of IB-DNQ with anti-PD-L1 eradicates well-established and checkpoint blockade refractory tumors. Citation Format: Lingxiang Jiang, Paul J. Hergenrother, Xiumei Huang. Tumor selective immunotherapy to overcome checkpoint blockade resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1657.