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  3. Macrophage mitochondrial fission improves cancer cell phagocytosis induced by therapeutic antibodies and is impaired by glutamine competition

Macrophage mitochondrial fission improves cancer cell phagocytosis induced by therapeutic antibodies and is impaired by glutamine competition

  • Nat Cancer. 2022 Apr;3(4):453-470. doi: 10.1038/s43018-022-00354-5.
Jiang Li  # 1 2 3,  Yingying Ye  # 1 2,  Zhihan Liu  # 1 2,  Guoyang Zhang  # 4,  Huiqi Dai 1 2,  Jiaqian Li 1 2,  Boxuan Zhou 1 2,  Yihong Li 1 2,  Qiyi Zhao 5,  Jingying Huang 1 2,  Jingwei Feng 1 2,  Shu Liu 3,  Peigang Ruan 6,  Jinjing Wang 7,  Jiang Liu 1 2,  Min Huang 1 2,  Xinwei Liu 1 2,  Shubin Yu 1 2,  Ziyang Liang 4,  Liping Ma 4,  Xiaoxia Gou 6,  Guoliang Zhang 6,  Nian Chen 6,  Yiwen Lu 1 2,  Can Di 1 2,  Qidong Xia 1 2,  Jiayao Pan 1 2,  Ru Feng 8,  Qingqing Cai 9 10,  Shicheng Su 11 12 13 14 15
Affiliations

Affiliations

  • 1 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.
  • 2 Breast Tumour Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
  • 3 Department of Breast Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, China.
  • 4 Department of Hematology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
  • 5 Department of Infectious Diseases, Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
  • 6 Department of Head and Neck Oncology, Second Affiliated Hospital of Zunyi Medical University, Zunyi, China.
  • 7 Department of Pathology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.
  • 8 Department of Hematology, Nanfang Hospital of Southern Medical University, Guangzhou, China.
  • 9 State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 10 Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China.
  • 11 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. sushch@mail.sysu.edu.cn.
  • 12 Breast Tumour Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China. sushch@mail.sysu.edu.cn.
  • 13 Department of Infectious Diseases, Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China. sushch@mail.sysu.edu.cn.
  • 14 Biotherapy Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China. sushch@mail.sysu.edu.cn.
  • 15 Department of Immunology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China. sushch@mail.sysu.edu.cn.
  • # Contributed equally.
PMID: 35484420 DOI: 10.1038/s43018-022-00354-5
Abstract

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.

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