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NF-κB Activator 1 downregulation in macrophages activates STAT3 to promote adenoma-adenocarcinoma transition and immunosuppression in colorectal cancer

BACKGROUND: Adenoma-adenocarcinoma transition is a key feature of colorectal cancer (CRC) occurrence and is closely regulated by tumor-associated macrophages (TAMs) and CD8(+) T cells. Here, we investigated the effect of the NF-κB activator 1 (Act1) downregulation of macrophages in the adenoma-adeno...

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Detalles Bibliográficos
Autores principales: Wang, Shunyi, Kuai, Yihe, Lin, Simin, Li, Li, Gu, Quliang, Zhang, Xiaohan, Li, Xiaoming, He, Yajun, Chen, Sishuo, Xia, Xiaoru, Ruan, Zhang, Lin, Caixia, Ding, Yi, Zhang, Qianqian, Qi, Cuiling, Li, Jiangchao, He, Xiaodong, Pathak, Janak L., Zhou, Weijie, Liu, Side, Wang, Lijing, Zheng, Lingyun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10053426/
https://www.ncbi.nlm.nih.gov/pubmed/36978108
http://dx.doi.org/10.1186/s12916-023-02791-0
Descripción
Sumario:BACKGROUND: Adenoma-adenocarcinoma transition is a key feature of colorectal cancer (CRC) occurrence and is closely regulated by tumor-associated macrophages (TAMs) and CD8(+) T cells. Here, we investigated the effect of the NF-κB activator 1 (Act1) downregulation of macrophages in the adenoma-adenocarcinoma transition. METHODS: This study used spontaneous adenoma-developing Apc(Min/+), macrophage-specific Act1-knockdown (anti-Act1), and Apc(Min/+); anti-Act1 (AA) mice. Histological analysis was performed on CRC tissues of patients and mice. CRC patients’ data retrieved from the TCGA dataset were analyzed. Primary cell isolation, co-culture system, RNA-seq, and fluorescence-activated cell sorting (FACS) were used. RESULTS: By TCGA and TISIDB analysis, the downregulation of Act1 expression in tumor tissues of CRC patients negatively correlated with accumulated CD68(+) macrophages in the tumor. Relative expression of EMT markers in the tumor enriched ACT1(low)CD68(+) macrophages of CRC patients. AA mice showed adenoma-adenocarcinoma transition, TAMs recruitment, and CD8(+) T cell infiltration in the tumor. Macrophages depletion in AA mice reversed adenocarcinoma, reduced tumor amounts, and suppressed CD8(+) T cell infiltration. Besides, macrophage depletion or anti-CD8a effectively inhibited metastatic nodules in the lung metastasis mouse model of anti-Act1 mice. CRC cells induced activation of IL-6/STAT3 and IFN-γ/NF-κB signaling and the expressions of CXCL9/10, IL-6, and PD-L1 in anti-Act1 macrophages. Anti-Act1 macrophages facilitated epithelial-mesenchymal-transition and CRC cells’ migration via CXCL9/10-CXCR3-axis. Furthermore, anti-Act1 macrophages promoted exhaustive PD1(+) Tim3(+) CD8(+) T cell formation. Anti-PD-L1 treatment repressed adenoma-adenocarcinoma transition in AA mice. Silencing STAT3 in anti-Act1 macrophages reduced CXCL9/10 and PD-L1 expression and correspondingly inhibited epithelial-mesenchymal-transition and CRC cells’ migration. CONCLUSIONS: Act1 downregulation in macrophages activates STAT3 that promotes adenoma-adenocarcinoma transition via CXCL9/10-CXCR3-axis in CRC cells and PD-1/PD-L1-axis in CD8(+) T cells. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12916-023-02791-0.