IL-33 from senescent hepatic stellate cells promotes obesity-associated liver cancer development by suppressing antitumor immunity

  Obesity is known to be a risk factor for several types of cancer including hepatocellular carcinoma (HCC).  We have previously shown that the increased level of deoxycholic acid (DCA), a obesity-induced gut microbial... [ view full abstract ]

  Obesity is known to be a risk factor for several types of cancer including hepatocellular carcinoma (HCC).  We have previously shown that the increased level of deoxycholic acid (DCA), a obesity-induced gut microbial metabolite, induces the cellular senescense of hepatic stellate cells (HSCs) through enterohepatic circulation. Moreover, this cellular senescece of HSCs was accompanyed by the production of tumor-promoting factors such as inflammatory cytokines, a phenomenon called senescence-associated secretory phenotype (SASP), which can promote the development of obesity-associated HCC.  In the present study, we investigated which cytokine produced by HSCs contributed to the obesity-associated HCC development.  We found that IL-33, a IL-1 family cytokine, was highly expressed in the liver tumor region and its expression was originated from the DCA-induced senescent HSCs in the tumor areas.  Interestingly, IL-33-deficient mice developmed less tumors compared with those in wild-type mice, suggesting that IL-33 plays an important role in promoting the obesity-associated HCC.  In the obese mice liver, the population of regulatory T cells (Tregs) expressing ST2, a receptor for IL-33, was significantly increased, and more interestingly, the ST2-deficient mice also showed less liver tumor development, coinciding with the results using IL-33 deficient mice.  Emerging evidences suggest that the activation of Tregs has crucial roles in tumor development by suppressing anti-tumor immune responses.  Our findings suggest that senescencet HSC-derived IL-33 could suppress anti-tumor immunity by activating ST2⁺ Tregs and contributes to promote the obesity-associated HCC development.