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

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-κB and interferon reporter cell lines to identify 4H-chromene-3-carbonitriles as a class of compounds that prolonge...

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Main Authors:	Fumi Sato-Kaneko, Xiaodong Wang, Shiyin Yao, Tadashi Hosoya, Fitzgerald S. Lao, Karen Messer, Minya Pu, Nikunj M. Shukla, Howard B. Cottam, Michael Chan, Dennis A. Carson, Maripat Corr, Tomoko Hayashi
Format:	Article
Language:	English
Published:	Hindawi Limited 2018-01-01
Series:	BioMed Research International
Online Access:	http://dx.doi.org/10.1155/2018/8091283

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spelling	doaj-d1711a60b8a546bba580f1f87ced90ae2020-11-24T20:45:32ZengHindawi LimitedBioMed Research International2314-61332314-61412018-01-01201810.1155/2018/80912838091283Discovery of a Novel Microtubule Targeting Agent as an Adjuvant for Cancer ImmunotherapyFumi Sato-Kaneko0Xiaodong Wang1Shiyin Yao2Tadashi Hosoya3Fitzgerald S. Lao4Karen Messer5Minya Pu6Nikunj M. Shukla7Howard B. Cottam8Michael Chan9Dennis A. Carson10Maripat Corr11Tomoko Hayashi12Moores Cancer Center, University of California San Diego, La Jolla 92093, USAMoores Cancer Center, University of California San Diego, La Jolla 92093, USAMoores Cancer Center, University of California San Diego, La Jolla 92093, USAMoores Cancer Center, University of California San Diego, La Jolla 92093, USAMoores Cancer Center, University of California San Diego, La Jolla 92093, USADivision of Biostatistics, University of California San Diego, La Jolla 92093, USADivision of Biostatistics, University of California San Diego, La Jolla 92093, USAMoores Cancer Center, University of California San Diego, La Jolla 92093, USAMoores Cancer Center, University of California San Diego, La Jolla 92093, USAMoores Cancer Center, University of California San Diego, La Jolla 92093, USAMoores Cancer Center, University of California San Diego, La Jolla 92093, USADepartment of Medicine, University of California San Diego, La Jolla 92093, USAMoores Cancer Center, University of California San Diego, La Jolla 92093, USAFor 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-κB 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.http://dx.doi.org/10.1155/2018/8091283
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Fumi Sato-Kaneko Xiaodong Wang Shiyin Yao Tadashi Hosoya Fitzgerald S. Lao Karen Messer Minya Pu Nikunj M. Shukla Howard B. Cottam Michael Chan Dennis A. Carson Maripat Corr Tomoko Hayashi
spellingShingle	Fumi Sato-Kaneko Xiaodong Wang Shiyin Yao Tadashi Hosoya Fitzgerald S. Lao Karen Messer Minya Pu Nikunj M. Shukla Howard B. Cottam Michael Chan Dennis A. Carson Maripat Corr Tomoko Hayashi Discovery of a Novel Microtubule Targeting Agent as an Adjuvant for Cancer Immunotherapy BioMed Research International
author_facet	Fumi Sato-Kaneko Xiaodong Wang Shiyin Yao Tadashi Hosoya Fitzgerald S. Lao Karen Messer Minya Pu Nikunj M. Shukla Howard B. Cottam Michael Chan Dennis A. Carson Maripat Corr Tomoko Hayashi
author_sort	Fumi Sato-Kaneko
title	Discovery of a Novel Microtubule Targeting Agent as an Adjuvant for Cancer Immunotherapy
title_short	Discovery of a Novel Microtubule Targeting Agent as an Adjuvant for Cancer Immunotherapy
title_full	Discovery of a Novel Microtubule Targeting Agent as an Adjuvant for Cancer Immunotherapy
title_fullStr	Discovery of a Novel Microtubule Targeting Agent as an Adjuvant for Cancer Immunotherapy
title_full_unstemmed	Discovery of a Novel Microtubule Targeting Agent as an Adjuvant for Cancer Immunotherapy
title_sort	discovery of a novel microtubule targeting agent as an adjuvant for cancer immunotherapy
publisher	Hindawi Limited
series	BioMed Research International
issn	2314-6133 2314-6141
publishDate	2018-01-01
description	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-κB 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.
url	http://dx.doi.org/10.1155/2018/8091283
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Discovery of a Novel Microtubule Targeting Agent as an Adjuvant for Cancer Immunotherapy

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