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

Nature communications (2020-02-01)
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, Kouji Matsushima
RÉSUMÉ

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.

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Diethyl 1,4-dihydro-2,4,6-trimethyl-3,5-pyridinedicarboxylate, 99%
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cis-11-Methyl-2-dodecenoic acid, ≥90.0% (HPLC)