Non-alcoholic steatohepatitis (NASH), a common condition in obese patients, is an important risk factor for HCC. However, only little information exists about the immunological mechanisms of how NASH promotes hepatocarcinogenesis. Methionine choline deficient (MCD) diet is widely used to induce NASH. In this study we fed Lap-tTA-myc mice, which develop HCC, with MCD diet. MCD diet accelerated tumor development in MYC on mice. A robust decrease of hepatic CD4 but not CD8 T cells was observed in NASH mice, which was exacerbated by MYC transgene expression. As expected higher level of cell death was detected in these hepatic CD4 T cells. Phenotypic analysis demonstrated that these CD4 T cells had a CD44highCD62Llow effector memory phenotype and produced more IFNγ. Selective CD4 T cell depletion further accelerated HCC development suggesting an important role of these cells for tumor development. Next, we studied the cause of CD4 T cells. In co-culture experiments we demonstrated that lipid-laden hepatocytes from mice on MCD diet induced selective CD4 but not CD8 T cells death through a contact-independent mechanism. FFAs were found from hepatocyte culture medium, and linoleic acid recapitulates the selective toxicity to CD4 T cells. Blocking ROS abolished linoleic acid-induced CD4 T cell death. Our results suggest the critical role of CD4 T cell in the disease progression of NASH to HCC, and provide a new link between lipid metabolism dysfunction with impaired anti-tumor surveillance.
Citation Format: Chi Ma, Miaojun Han, Masaki Terabe, Jay Berzofsky, Dean Felsher, Tim Greten. The role of CD4 T cells in murine model of NASH-promoted HCC. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B44.
- ©2015 American Association for Cancer Research.