NF-κB Activator 1 downregulation in macrophages activates STAT3 to promote adenoma-adenocarcinoma transition and immunosuppression in colorectal cancer
Shunyi Wang,
Yihe Kuai,
Simin Lin,
Li Li,
Quliang Gu,
Xiaohan Zhang,
Xiaoming Li,
Yajun He,
Sishuo Chen,
Xiaoru Xia,
Zhang Ruan,
Caixia Lin,
Yi Ding,
Qianqian Zhang,
Cuiling Qi,
Jiangchao Li,
Xiaodong He,
Janak L. Pathak,
Weijie Zhou,
Side Liu,
Lijing Wang,
Lingyun Zheng
Affiliations
Shunyi Wang
School of Life Science and Biopharmaceutics, Guangdong Pharmaceutical University
Yihe Kuai
School of Life Science and Biopharmaceutics, Guangdong Pharmaceutical University
Simin Lin
Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University
Li Li
School of Life Science and Biopharmaceutics, Guangdong Pharmaceutical University
Quliang Gu
School of Life Science and Biopharmaceutics, Guangdong Pharmaceutical University
Xiaohan Zhang
Hospital of Guangdong Provincial Hospital of Traditional Chinese Medicine
Xiaoming Li
Department of Pathology, People’s Hospital of Shenzhen Bao an District
Yajun He
Department of Pathology, People’s Hospital of Shenzhen Bao an District
Sishuo Chen
School of Life Science and Biopharmaceutics, Guangdong Pharmaceutical University
Xiaoru Xia
School of Life Science and Biopharmaceutics, Guangdong Pharmaceutical University
Zhang Ruan
School of Life Science and Biopharmaceutics, Guangdong Pharmaceutical University
Caixia Lin
School of Life Science and Biopharmaceutics, Guangdong Pharmaceutical University
Yi Ding
School of Life Science and Biopharmaceutics, Guangdong Pharmaceutical University
Qianqian Zhang
School of Life Science and Biopharmaceutics, Guangdong Pharmaceutical University
Cuiling Qi
School of Life Science and Biopharmaceutics, Guangdong Pharmaceutical University
Jiangchao Li
School of Life Science and Biopharmaceutics, Guangdong Pharmaceutical University
Xiaodong He
School of Life Science and Biopharmaceutics, Guangdong Pharmaceutical University
Janak L. Pathak
Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University
Weijie Zhou
Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, First Clinical Medical School, Southern Medical University
Side Liu
Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University
Lijing Wang
School of Life Science and Biopharmaceutics, Guangdong Pharmaceutical University
Lingyun Zheng
School of Life Science and Biopharmaceutics, Guangdong Pharmaceutical University
Abstract 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 ApcMin/+, macrophage-specific Act1-knockdown (anti-Act1), and ApcMin/+; 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 ACT1lowCD68+ 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.