Apolipoprotein C-III itself stimulates the Syk/cPLA2-induced inflammasome activation of macrophage to boost anti-tumor activity of CD8+ T cell

Increased prevalence of cancer in obese individuals is involved with dyslipidemia- induced chronic inflammation and immune suppression. Although apolipoprotein C-III (ApoC3)-transgenic mice (ApoC3(TG) mice) or poloxamer 407 (P407)-treated mice had hyperlipidemia, CD8(+) T cells with upregulated antitumor activities were observed in ApoC3(TG) mice, and decreased CD8(+) T cell activities were observed in P407-treated mice. Increased ApoC3 expression in hepatocellular carcinoma was associated with increased infiltration of CD8(+) T cells and predicted survival. Recombinant ApoC3 had no direct effects on CD8(+) T cells. The upregulation of CD8(+) T cells in ApoC3TG mice was due to cross-talk with context cells, as indicated by metabolic changes and RNA sequencing results. In contrast to dendritic cells, the macrophages of ApoC3(TG) mice (macrophages(TG)) displayed an activated phenotype and increased IL-1 beta, TNF-alpha, and IL-6 production. Coculture with macrophages(TG) increased CD8(+) T cell function, and the adoptive transfer of macrophages(TG) suppressed tumor progression in vivo. Furthermore, spleen tyrosine kinase (Syk) activation induced by TLR2/TLR4 cross-linking after ApoC3 ligation promoted cellular phospholipase A2 (cPLA2) activation, which in turn activated NADPH oxidase 2 (NOX2) to promote an alternative mode of inflammasome activation. Meanwhile, mitochondrial ROS produced by increased oxidative phosphorylation of free fatty acids facilitated the classical inflammasome activation, which exerted an auxiliary effect on inflammasome activation of macrophages(TG). Collectively, the increased antitumor activity of CD8(+) T cells was mediated by the ApoC3-stimulated inflammasome activation of macrophages, and the mimetic ApoC3 peptides that can bind TLR2/4 could be a future strategy to target liver cancer.

Automated summary

The increased prevalence of cancer in obese individuals is linked to chronic inflammation and immune suppression caused by dyslipidemia. This study found that apolipoprotein C-III (ApoC3) is associated with the activation of CD8(+) T cells in hepatocellular carcinoma, enhancing their antitumor activities through the stimulation of inflammasome activation in macrophages. This discovery may provide a potential new strategy for targeting liver cancer using mimetic ApoC3 peptides.