Background/Aims The identification of factors that lead to CD8+ T cell dysfunction within the tumor microenvironment (TME) holds great promise for the development of innovative immunotherapies. However, the mechanisms underlying the exhausted phenotype of CD8+ T cells infiltrating early-stage hepatocellular carcinoma (HCC) tumors remain unclear.
Methods Single-cell RNA sequencing was performed using a murine HCC model. Flow cytometry and additional experimental approaches were employed to investigate the mechanisms of CD8+ T cell exhaustion.
Results CD8+ T cells infiltrating early-stage HCC exhibited a functionally exhausted phenotype, which escalated with HCC progression. At early stages of HCC, the TME was characterized by significant iron accumulation. Moreover, tumor-infiltrating CD8+ T cells in murine HCC exhibited higher levels of intracellular ferrous iron compared to splenic CD8+ T. This excessive iron led to increased lipid peroxide levels and impaired the effector function of CD8+ T cells. Mechanistically, CD36 upregulated the iron uptake protein transferrin receptor 1 (TfR1) by mediating the activation of oxidized low-density lipoprotein (oxLDL)-p38-CEBPB axis. Depletion of CD36 in CD8+ T cells inhibited the upregulation of TfR1 and the increase of iron levels. Furthermore, constitutively activated nuclear factor erythroid 2-related factor 2 (NRF2) effectively suppressed lipid peroxidation, thereby preserving the effector functions of intratumoral CD8+ T cells and ultimately inhibiting tumor growth.
Conclusions Our findings reveal a previously unidentified mechanism mediated by CD36 that regulates the progressive dysfunction of CD8+ T cells in early HCC TME and provide a potential novel therapeutic approach to restore T cell function.
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Background/Aims .' Oxidative stress is known to play a role in the pathogenesis of a certain liver diseases such as alcoholic liver disease, metal storage disease, and ischemia/reperfusion injury. Recently oxidative stress(lipid peroxidation) has also been implicated in hepatic fibrosis, which is now regarded as a common response to chronic liver injury regardless of its nature. Development of fibrosis and cirrhosis are the major complications of chronic hepatitits B. So we aimed to detect lipid peroxidation in chronic hepatitis B and to investigate its potential role in the pathophysiology of the disease. Methods .' The subjects were histologically-proven 56 patients, including fatty liver(FL, n=8), healthy HBsAg carrier(n=6), chronic persistent hepatitis(CPH, n=8), mild chronic active hepatitis(CAH- m, n=10), severe CAH(CAH-s, n=16), and liver cirrhosis(LC, n=8). All patients were serologically HBsAg-positive except those with FL. Lipid peroxidation was detected in serum and liver specimen with TBARS(thiobarbituric acid-reacting substances) assay. Western blot and immunohistochemical stain of liver specimen were also performed, using polyclonal antibody against malondialdehyde (MDA). Results '. 1. There were no significant differences in serum TBARS levels among groups(p= 0.24). 2. The mean tissue TBARS level(nmol/g) was significantly higher in CAH-s group(175.4+ 41.5) than in other groups(FL 54.0+ 6.4, Carrier 51.1+ 15.9, CPH 63.9+ 2.9, CAH-m 68.9+ 7.9, LC 22.6+ 5.1) (p<0.05). 3. Tissue TBARS levels correlated with serum ALT levels(r=0.5934, p<0.05). 4. Western blot showed MDA bands only in CAH-s group. 5. Immunohistochemistry showed a strong MDA stain around portal and periportal area in CAH-s group, but weak or no stain in other groups. Conclusions . This study shows that lipid peroxidation can be detected in situ and commonly occurs in severe chronic hepatitis B. Oxidative stress may be related to active necroinflammatory change of the liver and contribute to the progression of the disease in chronic hepatitis B.
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