Credit: Carl Conway/Macmillan Publishers Limited

While it is well established that activated immune cells can eradicate established tumours, the processes involved in immune surveillance and control of cancer development are less clear. A new study published in Nature now demonstrates that immunoglobulin A (IgA)-producing (IgA+) cells, which accumulate in the livers of patients and mice with nonalcoholic steatohepatitis (NASH) and suppress activation of cytotoxic CD8+ T cells, can be therapeutically targeted with anti-programmed cell death 1 ligand 1 (PDL1) therapy to reduce progression of NASH to hepatocellular carcinoma (HCC).

Using mouse models of NASH-driven HCC, Shalapour et al. investigated the functional link between increased circulating IgA levels in NASH patients and the interference of IgA+ cells with cytotoxic CD8+ T cell activation. Transgenic mice that express urokinase-type plasminogen activator (uPA) driven by a hepatocyte-specific promoter for major urinary protein (MUP) (MUP-uPA mice) develop NASH and fibrosis. When fed a high-fat diet (HFD), NASH-bearing MUP-uPA mice had increased circulating IgA levels and liver IgA+ cell infiltration than those fed a normal-fat diet. These liver IgA+ cells were mainly plasma cells or plasmablasts. Interestingly, most IgA+ plasmocytes in the livers of MUP-uPA mice and patients with NASH expressed high levels of PDL1 and interleukin-10 (IL10).

the generation of IgA+ plasmocytes requires PDL1 activity

The researchers generated MUP-uPA mice deficient for IgA (MUP-uPA;Iga−/−), in which IgA+PDL1+IL10+ plasmocytes were abolished but steatosis was unaffected. Similarly, steatosis in MUP-uPA mice deficient for CD8 (MUP-uPA;CD8a−/−), in which CD8+ T cells were abolished, was unaffected. When fed a HFD, NASH to HCC progression in MUP-uPA mice occured after 7 months. Importantly, MUP-uPA;CD8a−/− mice developed HCC earlier than MUP-uPA mice, whereas MUP-uPA;Iga−/− mice developed HCC with significant delay, with some being tumour-free even after 11 months of a HFD. When analysing CD8+ T cell infiltration in livers of MUP-uPA;Iga−/− mice, the researchers found an increasing number of activated CD8+ T cells over time. By contrast, the number of activated CD8+ T cells in MUP-uPA mice decreased over time and was consistently lower than in MUP-uPA;Iga−/− mice, indicating that IgA+ plasmocytes suppress activation of CD8+ T cells. When treating HFD-fed, tumour-bearing MUP-uPA mice with a PDL1-blocking antibody, the tumour burden was significantly reduced after 8 weeks, lymphocyte accumulation in the tumour increased and steatosis decreased. The number of IgA+PDL1+IL10+ plasmocytes in the livers of these mice was decreased, likely due to a disrupted maturation process. By contrast, neither MUP-uPA;Iga−/− mice nor MUP-uPA;CD8a−/− mice responded to PDL1 blockade with reduced tumour growth, indicating that the generation of IgA+ plasmocytes requires PDL1 activity.

Collectively, this research highlights that effective liver immunosurveillance is disrupted during chronic inflammation when IgA+ plasmocyte infiltration in the liver is increased. Moreover, these findings broaden the application range of anti-PDL1 therapy, which could potentially prevent HCC progression in patients with NASH by targeting immunosuppressive IgA+ cells, thereby enhancing liver cytotoxic CD8+ T cell activation.