Chronic inflammation may promote hepatocellular carcinoma by suppressing cytotoxic T-cell activity.

  • Major finding: Chronic inflammation may promote hepatocellular carcinoma by suppressing cytotoxic T-cell activity.

  • Mechanism: Inflammation induces accumulation of IgA+ cells that suppress CD8+ T-cell activity and tumorigenesis.

  • Impact: PD-1 blockade warrants further investigation for treatment of patients with fibrosis-induced liver cancer.


The role of the adaptive immune system in early tumorigenesis is not well understood. Hepatocellular carcinoma (HCC) can be initiated by chronic inflammation driven by nonalcoholic steatohepatitis (NASH), and these patients exhibit an increase in IgA+ cells, which are inflammation-associated cells generated from a TGFβ-mediated conversion from IgM-expressing B cells, that interfere with the activation of cytotoxic CD8+ T cells. Shalapour and colleagues investigated the role of adaptive immunity in HCC development in the context of NASH. NASH induced an accumulation of IgA+ cells in the fibrotic liver in both human patients and mouse models and was associated with an increase in CD8+ T cells, and after progression to HCC the levels of IgA+ cells and CD8+ T cells in the liver remained elevated. The IgA+ cells predominantly expressed high levels of PD-L1 and IL10. Loss of IgA+ cells suppressed HCC tumorigenesis in a mouse model of NASH, whereas loss of CD8+ T cells accelerated HCC formation. Mechanistically, liver IgA+ cells induced cytotoxic CD8+ T-cell exhaustion, suppressing their activity and antitumor immunity to enhance HCC tumorigenesis. An anti–PD-L1 antibody induced tumor regression in mice with HCC by reducing the abundance of liver IgA+PD-L1+IL10+ cells to promote reactivation and expansion of antigen-specific CD8+ T cells. Taken together, these results elucidate a role for adaptive immunity in suppressing HCC tumorigenesis and demonstrate that the immunosuppressive effects of IgA+ cells are required for the transition for NASH to HCC. Further, these findings suggest that PD-1 blockade may be effective in patients with early HCC.

Shalapour S, Lin XJ, Bastian IN, Brain J, Burt AD, Aksenov AA, et al. Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity. Nature 2017;551:340–5.

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