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  • Title: PD-L1 promotes colorectal cancer stem cell expansion by activating HMGA1-dependent signaling pathways.
    Author: Wei F, Zhang T, Deng SC, Wei JC, Yang P, Wang Q, Chen ZP, Li WL, Chen HC, Hu H, Cao J.
    Journal: Cancer Lett; 2019 May 28; 450():1-13. PubMed ID: 30776481.
    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 × 104 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.
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