Discovery of a Novel Microtubule Targeting Agent as an Adjuvant for Cancer Immunotherapy

作者：Sato-Kaneko, Fumi; Wang, Xiaodong; Yao, Shiyin; Hosoya, Tadashi; Lao, Fitzgerald S.; Messer, Karen; Pu, Minya; Shukla, Nikunj M.; Cottam, Howard B.; Chan, Michael; Carson, Dennis A.; Corr, Maripat; Hayashi, Tomoko^*

来源：Biomed Research International, 2018, 2018: 8091283.

DOI：10.1155/2018/8091283

• NF-KAPPA-B
• DENDRITIC CELLS
• ANTIPROLIFERATIVE NAPHTHOPYRAN
• ANTITUMOR IMMUNITY
• CROSS-PRESENTATION
• BONE-MARROW
• CYTOSKELETON
• ACTIVATION
• KINASE
• SUPPRESSION

For an activating immunotherapy such as adjuvants, a compound that can prolong immune stimulation may enhance efficacy. We leveraged data from two prior high throughput screens with NF-kappa B and interferon reporter cell lines to identify 4H-chromene-3-carbonitriles as a class of compounds that prolonged activation in both screens. We repurchased 23 of the most promising candidates. Out of these compounds we found #1 to be the most effective agent in stimulating the release of cytokines and chemokines from immune cells, including murine primary bone marrow derived dendritic cells. Mechanistically, #1 inhibited tubulin polymerization, and its effect on immune cell activation was abolished in cells mutated in the beta-tubulin gene (TUBB) encoding the site where colchicine binds. Treatment with #1 resulted in mitochondrial depolarization followed by mitogen- activated protein kinase activation. Because tubulin polymerization modulating agents have been used for chemotherapy to treat malignancy and #1 activated cytokine responses, we hypothesized that #1 could be effective for cancer immunotherapy. Intratumoral injection of #1 delayed tumor growth in a murine syngeneic model of head and neck cancer. When combined with PD-1 blockade, tumor growth slowed in the injected tumor nodule and there was an abscopal effect in an uninjected nodule on the contralateral flank, suggesting central antitumor immune activation. Thus, we identified a new class of tubulin depolymerizing agent that acts as both an innate and an adaptive immune activating agent and that limits solid tumor growth when used concurrently with a checkpoint inhibitor.

• 出版日期2018
• 单位深圳大学