Targeting FROUNT with disulfiram suppresses macrophage accumulation and its tumor-promoting properties

Yuya Terashima (), Etsuko Toda, Meiji Itakura, Mikiya Otsuji, Sosuke Yoshinaga, Kazuhiro Okumura, Francis H. W. Shand, Yoshihiro Komohara, Mitsuhiro Takeda, Kana Kokubo, Ming-Chen Chen, Sana Yokoi, Hirofumi Rokutan, Yutaka Kofuku, Koji Ohnishi, Miki Ohira, Toshihiko Iizasa, Hirofumi Nakano, Takayoshi Okabe, Hirotatsu Kojima, Akira Shimizu, Shiro Kanegasaki, Ming-Rong Zhang, Ichio Shimada, Hiroki Nagase, Hiroaki Terasawa and Kouji Matsushima
Additional contact information
Yuya Terashima: Tokyo University of Science
Etsuko Toda: Tokyo University of Science
Meiji Itakura: Chiba Cancer Center
Mikiya Otsuji: The University of Tokyo
Sosuke Yoshinaga: Kumamoto University
Kazuhiro Okumura: Chiba Cancer Center Research Institute
Francis H. W. Shand: The University of Tokyo
Yoshihiro Komohara: Kumamoto University
Mitsuhiro Takeda: Kumamoto University
Kana Kokubo: Tokyo University of Science
Ming-Chen Chen: Tokyo University of Science
Sana Yokoi: Chiba Cancer Center Research Institute
Hirofumi Rokutan: The University of Tokyo
Yutaka Kofuku: The University of Tokyo
Koji Ohnishi: Kumamoto University
Miki Ohira: Chiba Cancer Center Research Institute
Toshihiko Iizasa: Chiba Cancer Center
Hirofumi Nakano: The University of Tokyo
Takayoshi Okabe: The University of Tokyo
Hirotatsu Kojima: The University of Tokyo
Akira Shimizu: Nippon Medical School
Shiro Kanegasaki: National Center for Global Health and Medicine
Ming-Rong Zhang: National Institutes for Quantum and Radiological Science and Technology
Ichio Shimada: The University of Tokyo
Hiroki Nagase: Chiba Cancer Center Research Institute
Hiroaki Terasawa: Kumamoto University
Kouji Matsushima: Tokyo University of Science

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract Tumor-associated macrophages affect tumor progression and resistance to immune checkpoint therapy. Here, we identify the chemokine signal regulator FROUNT as a target to control tumor-associated macrophages. The low level FROUNT expression in patients with cancer correlates with better clinical outcomes. Frount-deficiency markedly reduces tumor progression and decreases macrophage tumor-promoting activity. FROUNT is highly expressed in macrophages, and its myeloid-specific deletion impairs tumor growth. Further, the anti-alcoholism drug disulfiram (DSF) acts as a potent inhibitor of FROUNT. DSF interferes with FROUNT-chemokine receptor interactions via direct binding to a specific site of the chemokine receptor-binding domain of FROUNT, leading to inhibition of macrophage responses. DSF monotherapy reduces tumor progression and decreases macrophage tumor-promoting activity, as seen in the case of Frount-deficiency. Moreover, co-treatment with DSF and an immune checkpoint antibody synergistically inhibits tumor growth. Thus, inhibition of FROUNT by DSF represents a promising strategy for macrophage-targeted cancer therapy.

Date: 2020
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DOI: 10.1038/s41467-020-14338-5

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