Loss of fragile site-associated tumor suppressor promotes antitumor immunity via macrophage polarization
| Autor: | Yurong Da, Xiangdong Guo, Guangze Yang, Lijuan Zhang, Hongkun Liu, Qing Xi, Dongmei Zhou, Yan Li, Qi Zhang, Li Liu, Jinrong Zhu, Jieyou Zhang, Rongxin Zhang, Huafeng Wang, Zhenyi Xue, Yingnan Cheng, Zhinan Yin, Zimu Zhang, Kai Zhang, Zhi Yao |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Science medicine.medical_treatment Macrophage polarization General Physics and Astronomy Cancer immunotherapy Cell Cycle Proteins Article General Biochemistry Genetics and Molecular Biology Mice 03 medical and health sciences 0302 clinical medicine Immune system NF-KappaB Inhibitor alpha Cell Line Tumor Neoplasms medicine Animals Humans Macrophage Cytotoxic T cell Tumour-suppressor proteins Monocytes and macrophages Multidisciplinary Chemistry Macrophages Tumor Suppressor Proteins Chromosomal fragile site NF-kappa B General Chemistry Macrophage Activation Th1 Cells IκBα 030104 developmental biology 030220 oncology & carcinogenesis Ubiquitin-Conjugating Enzymes Cancer cell Cancer research Tumour immunology Immunotherapy Signal Transduction T-Lymphocytes Cytotoxic |
| Zdroj: | Nature Communications Nature Communications, Vol 12, Iss 1, Pp 1-17 (2021) |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-021-24610-x |
| Popis: | 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. The role of common fragile site associated genes such as FATS in the immune system is unclear. Here the authors show that deletion of Fats in a mouse tumour model leads to reduced tumour growth and change of macrophage phenotype from an M2-like to M1-like function. |
| Databáze: | OpenAIRE |
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