PTBP2-mediated alternative splicing of IRF9 controls tumor-associated monocyte/macrophage chemotaxis and repolarization in neuroblastoma progression

Authors：Tang, Jue; He, Jing; Guo, Huiqin; Lin, Huiran; Li, Meng; Yang, Tianyou; Wang, Hai-Yun; Li, Di; Liu, Jiabin; Li, Le; Xia, Huimin^*; Zhuo, Zhenjian^*; Miao, Lei^*

Source：Research, 2023, 2023: 0033.

DOI：10.34133/research.0033

• neuroblastoma
• tumor environment
• tumor-associated macrophages
• PTBP2
• alternative splicing

The recurrence and metastasis of children with throactic neuroblastoma (NB) are also occurred after surgery, chemotherapy or radiotherapy. Strategies targeting the tumor microenvironment (TME) have been reported to improve survival, however, thorough investigations of monocytes and tumor-associated macrophages (TAMs) with specialized functions in NB are still lacking. Our data first demonstrated PTBP2 as a possible identifier in thoracic NB patients screened by proteomic profiling and that PTBP2 predicted good outcomes. Functional studies revealed that PTBP2 in NB cells induced the chemotactic activity and repolarization of tumor-associated monocytes and macrophages (M phi s), which in turn inhibited NB growth and dissemination. Mechanistically, PTBP2 prevents IRF9 alternative splicing, upregulates STAT1 to stimulate CCL5 and ISGF-dependent IFN-I secretion, to induce monocyte/M rectangle s chemotaxis and sustain monocytes in a proinflammatory phenotype. Our study defined a critical event of PTBP2-induced monocytes/M rectangle s in NB progression and revealed that RNA splicing occurred by PTBP2 benefits immune compartmentalization between NB cells and monocytes. This work revealed the pathological and biological role of PTBP2 in NB development and indicates that PTBP2-induced RNA splicing benefits immune compartmentalization and predicted a favorable prognosis in thoracic NB

• Institution
  广州医学院; 北京大学