Cell cycle-related kinase reprograms the liver immune microenvironment to promote cancer metastasis

Liver Immune Microenvironment and Metastasis from Colorectal Cancer-Pathogenesis and Therapeutic Perspectives

“…Another study further pointed out that gut microbiome used bile acids as a signal to regulate LSEC-derived CXCL16 which recruited NKT cells in liver [98]. Consistently, our recent study demonstrated that CCRK-CXCL1-MDSC axis activation promoted CRC liver metastasis through suppression of anti-tumor hepatic NKT cells, while depletion of MDSC could restore hepatic NKT cells and reduce CRC liver metastasis [43]. In comparison, some controversial studies also pointed out that NKT cells exacerbated liver metastasis arising from intraocular melanomas by inhibiting the anti-tumor activity of liver NK cells [99].…”

“…Increased CXCL1 recruited PMN-MDSC and reduced natural killer T (NKT) cells in liver to form the pre-metastatic niche for melanoma and colorectal cancer liver metastasis in CCRK transgenic mice. Accordingly, CRC liver metastasis patients exhibited hyperactivation of hepatic CCRK/NF-κB/CXCL1 signaling, which was associated with accumulation of PMN-MDSCs and a paucity of NKT cells compared to healthy liver transplantation donors [ 43 ] ( Figure 1 ). This study highlighted the parenchymal-immune cell crosstalk in shaping the liver immune microenvironment for CRC liver metastasis.…”

“…Our previous study also found that CCRK-CXCL1 mediated PMN-MDSC recruitment in liver and reduced NKT cell infiltration were significantly correlated with melanoma and CRC liver metastasis. Inhibition of PMN-MDSC restored NKT cell infiltration and ameliorated liver metastasis [ 43 ]. In a mouse colon cancer and lung cancer liver metastasis model, accumulation of MDSC was associated with liver metastasis dependent on TNFR2 signaling.…”

“…Knockout C crk in mouse hepatoma significantly enhances the efficacy of immune checkpoint inhibitor by disrupting immunosuppression and unleashing anti-tumor immune response [ 135 , 136 ]. In addition, the ectopic expression of CCRK induced by chronic inflammation in liver shapes the immune microenvironment by accumulating immunosuppressive PMN-MDSCs and reduced anti-tumor NKT cells to facilitate CRC liver metastasis [ 43 ]. Collectively, CCRK plays a pivotal role in regulating liver microenvironment.…”

Cancer-associated adipocytes as immunomodulators in cancer

“…Various cytokines, including IL-4, IL-13, IFN-γ and TNFα, are generated by NKT cells, thereby mediating either T helper 1 (Th1) or Th2 responses [89]. In colorectal cancer (CRC), the increase in tumor metastasis to the liver was lacking natural killer T (NKT) cells [90]. Moreover, probiotics can mediate the conversion of primary to secondary bile acids, thereby increasing the expression of CXCL16 in liver sinusoidal endothelial cells.…”