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
  • 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. [email protected].
  • 8. Key Laboratory of Immune Microenvironment and Diseases (Ministry of Education), Tianjin Medical University, Tianjin, China. [email protected].
  • # 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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