Li Jiang, Ye Yingying, Liu Zhihan, Zhang Guoyang, Dai Huiqi, Li Jiaqian, Zhou Boxuan, Li Yihong, Zhao Qiyi, Huang Jingying, Feng Jingwei, Liu Shu, Ruan Peigang, Wang Jinjing, Liu Jiang, Huang Min, Liu Xinwei, Yu Shubin, Liang Ziyang, Ma Liping, Gou Xiaoxia, Zhang Guoliang, Chen Nian, Lu Yiwen, Di Can, Xia Qidong, Pan Jiayao, Feng Ru, Cai Qingqing, Su Shicheng
Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
Breast Tumour Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
Nat Cancer. 2022 Apr;3(4):453-470. doi: 10.1038/s43018-022-00354-5. Epub 2022 Apr 28.
Phagocytosis is required for the optimal efficacy of many approved and promising therapeutic antibodies for various malignancies. However, the factors that determine the response to therapies that rely on phagocytosis remain largely elusive. Here, we demonstrate that mitochondrial fission in macrophages induced by multiple antibodies is essential for phagocytosis of live tumor cells. Tumor cells resistant to phagocytosis inhibit mitochondrial fission of macrophages by overexpressing glutamine-fructose-6-phosphate transaminase 2 (GFPT2), which can be targeted to improve antibody efficacy. Mechanistically, increased cytosolic calcium by mitochondrial fission abrogates the phase transition of the Wiskott-Aldrich syndrome protein (WASP)-Wiskott-Aldrich syndrome interacting protein (WIP) complex and enables protein kinase C-θ (PKC-θ) to phosphorylate WIP during phagocytosis. GFPT2-mediated excessive use of glutamine by tumor cells impairs mitochondrial fission and prevents access of PKC-θ to compartmentalized WIP in macrophages. Our data suggest that mitochondrial dynamics dictate the phase transition of the phagocytic machinery and identify GFPT2 as a potential target to improve antibody therapy.
吞噬作用对于许多已获批的以及有前景的针对各种恶性肿瘤的治疗性抗体的最佳疗效而言是必需的。然而，决定对依赖吞噬作用的疗法产生反应的因素在很大程度上仍然不清楚。在此，我们证明多种抗体诱导的巨噬细胞中的线粒体分裂对于活肿瘤细胞的吞噬作用至关重要。对吞噬作用具有抗性的肿瘤细胞通过过度表达谷氨酰胺-果糖-6-磷酸转氨酶2（GFPT2）来抑制巨噬细胞的线粒体分裂，而GFPT2可成为提高抗体疗效的靶点。从机制上讲，线粒体分裂导致的胞质钙增加消除了威斯科特-奥尔德里奇综合征蛋白（WASP）-威斯科特-奥尔德里奇综合征相互作用蛋白（WIP）复合物的相变，并使蛋白激酶C-θ（PKC-θ）在吞噬作用期间能够磷酸化WIP。肿瘤细胞通过GFPT2介导的对谷氨酰胺的过度利用会损害线粒体分裂，并阻止PKC-θ接近巨噬细胞中分隔的WIP。我们的数据表明线粒体动力学决定了吞噬机制的相变，并将GFPT2确定为改善抗体治疗的潜在靶点。
