Legumain-deficient macrophages promote senescence of tumor cells by sustaining JAK1/STAT1 activation

• Published in: Cancer letters 2020-03, Vol.472, p.40-49
• Main Authors: Shen, Long, Kang, Lichun, Wang, Dekun, Xun, Jing, Chen, Chuan'ai, Du, Lingfang, Zhang, Mianzhi, Gong, Junbo, Mi, Xue, Yue, Shijing, Zhang, Yuying, Song, Xiangrong, Xiang, Rong, Zhang, Zhujun, Tan, Xiaoyue
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Blood; Bone marrow; Bone marrow transplantation; Breast cancer; Cell activation; Cell culture; Cellular senescence; Clonal deletion; Experiments; Gene deletion; Genomics; IL-1β; Immune system; Janus kinase; Legumain; M1 polarization; Macrophages; Nitric-oxide synthase; Phenotypes; Proteins; Senescence; Stat1 protein; Therapeutic applications; Transplantation; Tumor cells; Tumor-associated macrophage; Tumors
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2019.12.013

Macrophages serve as the first line of communication between tumors and the rest of the immune system, and understanding the interplay between macrophage and tumor cells is essential for developing novel macrophage-based strategy against tumor. Here, we show that deletion of legumain in macrophages activates senescence of tumor cells. Macrophage derived IL-1β mediates the pro-senescent effect of Lgmn-/- macrophages since blockage of IL-1β reverses the senescence phenotype in both a coculture model of macrophage and tumor cells and an orthotopic mouse model of breast cancer. Sustained activation of JAK1/STAT1 signaling and increased iNOS were found in the tumor cell-cocultured Lgmn-/- macrophages, which were necessary for IL-1β expression and secretion. Applying a specific STAT1 agonist mimics the inductive effect of legumain deletion on IL-1β expression in macrophages, and the effect can be blocked via inhibition of iNOS. Legumain and integrin αvβ3 interact to prevent STAT1 signaling in macrophages, and blockage of integrin αvβ3 stimulates STAT1 activation. Therapeutically, transplantation of bone marrow from Lgmn-/- mice suppresses the malignant growth of tumor by upregulating tumor cell senescence. Therefore, our finding highlights legumain in macrophages as a potential therapeutic target for tumors. •Depletion of legumain in macrophages suppresses tumor growth and activates senescence in tumor cells.•Downregulation of legumain in macrophage leads to sustained activation of JAK1/STAT1 and pro-inflammatory phenotype.•Macrophage-derived IL-1β mediates the pro-senescence effect of Lgmn-/- macrophages on tumor cells.•Transplantation of Lgmn-/- bone marrow suppresses tumor growth through activating tumor senescence.