2. Academic Validation
  3. Loss of fragile site-associated tumor suppressor promotes antitumor immunity via macrophage polarization

Loss of fragile site-associated tumor suppressor promotes antitumor immunity via macrophage polarization

  • Nat Commun. 2021 Jul 14;12(1):4300. doi: 10.1038/s41467-021-24610-x.
Lijuan Zhang  # 1,  Kai Zhang  # 1,  Jieyou Zhang  # 1,  Jinrong Zhu 2,  Qing Xi 1,  Huafeng Wang 3,  Zimu Zhang 1,  Yingnan Cheng 1,  Guangze Yang 1,  Hongkun Liu 1,  Xiangdong Guo 1,  Dongmei Zhou 1,  Zhenyi Xue 1,  Yan Li 1,  Qi Zhang 4,  Yurong Da 1,  Li Liu 5,  Zhinan Yin 6,  Zhi Yao 1,  Rongxin Zhang 7 8
Affiliations

Affiliations

  • 1 Key Laboratory of Immune Microenvironment and Diseases (Ministry of Education), Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
  • 2 Guangdong Province Key Laboratory for Biotechnology Drug Candidates, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China.
  • 3 School of Life Science, Shanxi Normal University, Linfen, China.
  • 4 Institute of Integrative Medicines for Acute Abdominal Diseases, Nankai Hospital, Tianjin, China.
  • 5 Department of Radiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 6 The First Affiliated Hospital, Biomedical Translation Research Institute and Guangdong Province Key Laboratory of Molecular Immunology and Antibody Engineering, Jinan University, Guangzhou, China.
  • 7 Guangdong Province Key Laboratory for Biotechnology Drug Candidates, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China. rxzhang@gdpu.edu.cn.
  • 8 Key Laboratory of Immune Microenvironment and Diseases (Ministry of Education), Tianjin Medical University, Tianjin, China. rxzhang@gdpu.edu.cn.
  • # Contributed equally.
PMID: 34262035 DOI: 10.1038/s41467-021-24610-x
Abstract

Common fragile sites (CFSs) are specific breakage-prone genomic regions and are present frequently in Cancer cells. The (E2-independent) E3 ubiquitin-conjugating Enzyme FATS (fragile site-associated tumor suppressor) has antitumor activity in Cancer cells, but the function of FATS in immune cells is unknown. Here, we report a function of FATS in tumor development via regulation of tumor immunity. Fats-/- mice show reduced subcutaneous B16 melanoma and H7 pancreatic tumor growth compared with WT controls. The reduced tumor growth in Fats-/- mice is macrophage dependent and is associated with a phenotypic shift of macrophages within the tumor from tumor-promoting M2-like to antitumor M1-like macrophages. In addition, FATS deficiency promotes M1 polarization by stimulating and prolonging NF-κB activation by disrupting NF-κB/IκBα negative feedback loops and indirectly enhances both CD4+ T helper type 1 (Th1) and cytotoxic T lymphocyte (CTL) adaptive immune responses to promote tumor regression. Notably, transfer of Fats-/- macrophages protects mice against B16 melanoma. Together, these data suggest that FATS functions as an immune regulator and is a potential target in Cancer Immunotherapy.

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