Hepatitis develops into liver cancer with the help of immune cells

Chronic inflammation has long been known to contribute to malignant tumors, including liver cancer. It was previously believed that inflammation directly stimulated tumor cell differentiation and protected them from death. However, researchers at the University of California, San Diego — led by Michael Karin — have provided new evidence showing that chronic hepatitis promotes liver cancer through a different mechanism: by suppressing immune surveillance. The findings were published in Nature in November 2017.

Using a mouse model derived from the natural course of non-alcoholic steatohepatitis (NASH) — a chronic liver disease caused by fat accumulation that leads to liver damage, fibrosis, gene mutations, and eventually hepatocellular carcinoma — the researchers found that NASH-related gene mutations initially stimulate cytotoxic T cells to recognize and attack emerging tumor cells. However, chronic hepatitis simultaneously causes the accumulation of immunosuppressive lymphocytes known as IgA+ cells, which ultimately win the battle against the anti-tumor T cells.

IgA+ cells suppress cytotoxic CD8+ T lymphocytes through two key mechanisms: expressing Programmed Death Ligand 1 (PD-L1) and releasing interleukin-10. Once T cells are suppressed, liver tumors are free to form and grow. The study demonstrated this clearly — among 15 mice lacking anti-tumor cytotoxic T cells, 27% developed large liver tumors within 6 months. In contrast, mice with intact cytotoxic T cells developed no tumors, and mice without immunosuppressive IgA+ cells showed almost no tumor formation either, confirming that IgA+ cells are the critical factor allowing tumors to escape immune control.

The discovery of PD-L1's role in enabling IgA+ cells to suppress T cells points directly to a therapeutic target. When researchers used drugs or genetic engineering to inhibit PD-L1, IgA+ cells were eliminated from the liver and reactivated cytotoxic T cells were able to destroy tumors. This provides strong theoretical support for the use of PD-1 inhibitor drugs in liver cancer treatment.

Nivolumab (Opdivo) by Bristol-Myers Squibb became the first FDA-approved anti-tumor immune drug for hepatocellular carcinoma patients after sorafenib treatment. Several other PD-1 inhibitors — including pembrolizumab (Keytruda), durvalumab (Imfinzi), BeiGene's BGB-A317, and Hengrui's SHR-1210 — are currently in clinical trials for liver cancer treatment, reflecting the growing momentum behind immune checkpoint blockade as a strategy for this disease.