iNature
Dysregulation of immune surveillance is strongly associated with the development of hepatocellular carcinoma (HCC) driven by steatohepatitis (MASH) associated with metabolic dysfunction; However, the underlying mechanism is unknown.
2024年5月6日，暨南大学林雪嘉及尹芝南共同通讯在Molecular Cancer（IF=37）在线发表题为“Interleukin-21 receptor signaling promotes metabolic dysfunction-associated steatohepatitis-driven hepatocellular carcinoma by inducing immunosuppressive IgA+ B cells”的研究论文，该研究发现白细胞介素-21受体信号通过诱导免疫抑制性IgA+ B细胞促进代谢功能障碍相关的脂肪性肝炎驱动的肝细胞癌。 高IL-21R表达的HCC患者无复发生存期较差，TNM分期较晚，脂肪变性严重。 此外，IL-21R在小鼠肝脏肿瘤中表达上调。 特别是，IL-21R的抑制抑制了MASH驱动的肝癌发生，显著减少了脂质积累。
In the absence of IL-21R, activation of cytotoxic CD8+ T lymphocytes is enhanced due to a decrease in immunosuppressive IgA+ B cells. Mechanistically, the IL-21R-STAT1-c-Jun/c-Fos regulatory axis is activated in MASH-driven HCCs, thereby promoting Igha transcription, leading to the induction of IgA+ B cells. In conclusion, the study found that IL-21R exerts a pro-cancer role in MASH-driven hepatogenesis by inducing IgA+ B cells. Targeting IL-21R signaling is a potential cancer treatment strategy.
Studies have shown that MASH-driven HCC development is accompanied by the accumulation of immune cells in the tumor microenvironment and plays an important role in initiating, maintaining, or exacerbating the transition from MASH to HCC. Dysregulation of immune surveillance is considered to be one of the new mechanisms of mashdriven HCC. For example, liver macrophages Kupffer cells are the liver's first-line defenses; However, studies have shown that they lack efficient transformation in MASH, and in the tumor context of fibrosis and steatosis, they are likely to transform into tumor-associated macrophages (TAMs), thereby promoting the inflammatory response of tumors. In addition, other innate immune cells, such as dendritic cells (DCs) and natural killer (NK) cells, may also be involved in the process of MASH driving HCC. Notably, in the context of MASLD, adaptive CD8+ T cells play a central role in hepatocarcinomagenesis.
Recently, IL-15 produced in the liver microenvironment has been found to downregulate FOXO1 in CD8+ T cells, allowing it to acquire resident properties by upregulating CXCR6, thereby enabling CXCR6+PD1+CD8+ T cells to initiate self-invasive killing of hepatocytes, thereby triggering MASH and transition to HCC. In addition, anti-PD-1 therapy did not reduce the tumor burden in preclinical models of MASH-associated HCC, but instead led to the accumulation of CXCR6+PD1+CD8+ T cells, suggesting that these cells may be responsible for the lack of responsiveness of MASH-associated HCC to immune checkpoint inhibitors.
Compared to CD8+ T cells, naïve CD4+ T cells are more susceptible to the MASLD microenvironment, and they have a higher mortality rate due to the oxidative stress-related cytotoxic effects of free fatty acids. Thus, the loss of CD4+ T cells has led to the failure of cancer surveillance in MASHinduced HCC. However, regulatory T (Treg) cells, a subset of CD4+ T cells, are increased in mash-induced HCC liver and promote carcinogenesis by supporting the immunosuppressive microenvironment. Accumulating evidence demonstrates that inflammation-induced immunosuppressive IgA+ B cells disrupt anti-cancer immunity by inhibiting the activation of cytotoxic CD8+ T lymphocytes (CTLs) in MASH-driven HCC, but the mechanism by which they produce IgA+ B cells is unclear.
IL-21R-STAT1-c-Jun/c-Fos-IgA轴模型（图源自Molecular Cancer ）
Interleukin-21 (IL-21) is a member of the γ-chain (γc) cytokine family and is mainly produced by T cells and natural killer T cells (NKT). Its private receptor IL-21 receptor (IL-21R) activates Janus kinase (JAK) signaling and transcriptional activator (STAT) signaling upon ligand binding, and is expressed by a variety of immune cell subsets, including but not limited to B cells, T cells, NK cells, macrophages, and DCs. IL-21/IL-21R signaling plays a key role in the immune response and is involved in the regulation of inflammation in various acute and chronic inflammatory diseases, such as cancer. However, the role of IL-21/IL-21R in cancer development remains controversial and has not been extensively studied in faithful in vivo models. IL-21 was initially shown to be a growth and survival factor in human myeloma cell lines, which is mediated by activation of the JAK1/STAT3 signaling pathway. In addition, IL-21 has been shown to have immunosuppressive effects due to its ability to induce IL-10. However, numerous reports suggest that IL-21 promotes tumor clearance, rather than tumor survival, suggesting that IL-21 is a promising cancer immunotherapeutic agent.
Here, the study elucidates the role of IL-21R in MASH-driven HCC and the underlying mechanisms underlying the production of IgA+ B cells. The results showed that IL-21R exerts a pro-cancer effect by activating the IL-21R-STAT1-c-Jun/c-Fos regulatory axis, which leads to the production of immunosuppressive IgA+ B cells, thereby attenuating CTL activation during tumorigenesis in MASH-driven HCC. Therefore, IL-21R exerts a pro-cancer role in MASH-driven hepatocarcinomagenesis by inducing IgA+ B cells. Targeting IL-21R signaling is a potential cancer treatment strategy.
Original link:
https://doi.org/10.1186/s12943-024-02001-2
来源:iNature