PD-L1 promotes colorectal cancer stem cell expansion by activating HMGA1-dependent signaling pathways. (28th May 2019)

• Record Type: Journal Article
• Authors: Wei, Fang; Zhang, Tong; Deng, Shu-Chou; Wei, Jian-Chang; Yang, Ping; Wang, Qiang; Chen, Zhuan-Peng; Li, Wang-Lin; Chen, Hua-Cui; Hu, He; Cao, Jie
• Is Part Of: Cancer letters. Volume 450(2019)
• Page Start: 1
• Page End: 13
• Publication Date: 2019-05-28
• Subjects: PD-L1 -- Colorectal cancer (CRC) -- Cancer stem cells (CSCs) -- HMGA1; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2019.02.022
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: PD-L1 is critical for tumor cell escape from immune surveillance by inhibiting T cell function via the PD-1 receptor. Accumulating evidence demonstrates that anti-PD-L1 monoclonal antibodies might potently enhance antitumor effects in various tumors, but the effect of PD-L1 on colorectal cancer stem cells (CSCs) remains unclear. We observed high PD-L1 expression in CD133 + CD44 + colorectal CSCs and CSC-enriched tumorspheres. Altering PD-L1 expression promoted colorectal CSC self-renewal by increasing the expression of stemness genes, the CD133 + CD44 + cell population sizes and the ability to form tumorspheres. Additionally, PD-L1 expression was markedly increased in chemoresistant colorectal cancer (CRC) cells in vitro and in vivo. More importantly, PD-L1 enhanced CRC cell tumorigenicity in nude mice; the inoculation of 1 × 10 4 cells resulted in high tumor formation efficiency. Mechanistically, PD-L1 directly interacted with HMGA1, and HMGA1 upregulation by PD-L1 activated HMGA1-dependent pathways, including the PI3K/Akt and MEK/ERK pathways, and promoted CSC expansion. HMGA1 downregulation rescued the PD-L1-induced phenotypes, highlighting the role of HMGA1 in PD-L1-mediated colorectal CSC self-renewal. Moreover, PD-L1 expression was correlated with the expression of CSC markers and HMGA1 in clinical CRC specimens. Thus, PD-L1 could crucially contribute to the maintenance of CSC self-renewal by activating HMGA1-dependent signaling pathways. Highlights: PD-L1 promotes the expansion of colorectal CSCs by increasing HMGA1-dependent signaling. PD-L1 promotes colorectal CSCs self-renewal in vitro and in vivo. PD-L1 correlates with chemoresistance. We used mass spectrometry, CO-IP and GST-pull down to identify a new protein (HMGA1) that PD-L1 interacts with directly.