Hepatitis develops into liver cancer with the help of immune cells

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Chronic inflammation can cause a variety of malignant tumors including liver cancer. Previously, it was generally believed that inflammation directly affects tumor cells and stimulates their differentiation to protect them from death. University of California, San Diego Michael Karin and others found that chronic hepatitis stimulates liver cancer by suppressing immune surveillance. (Nature. 2017 Nov 08. doi: 10.1038 / nature24302)

Recently, immunotherapy represented by immune checkpoint inhibitors and adoptive T-cell therapy has achieved great success in tumor treatment. Prompt the significant effect of activated immune cells to eradicate tumors, but now we have not taken the role of immune surveillance or adaptive immunity in tumorigenesis seriously. This study provides the most powerful and direct evidence to support adaptive immunity to actively prevent liver cancer.

The researchers did not use the traditional engineered gene mutation-induced mouse model, but a mouse model derived from the natural course of non-alcoholic steatohepatitis (NASH). This tumor is more similar to human liver cancer. NASH is a chronic progressive liver disease caused by accumulation of fat in the liver. It can cause liver damage, fibrosis, and a large number of gene mutations, leading to cirrhosis, liver failure, and hepatocellular carcinoma.

The study found that NASH-related gene mutations can stimulate the immune system, including cytotoxic T cells, to recognize and attack emerging tumor cells; however, in humans and mice, chronic hepatitis also causes the accumulation of immunosuppressive lymphocyte IgA + cells .

In the battle of two immune cells, IgA + cells and cytotoxic T cells, immunosuppressive lymphocytes win. IgA + cells express Programmed Death Ligand 1 (PD-L1) and interleukin-10, and directly inhibit hepatotoxic CD8 + T lymphocytes through PD-L1. After T cells are suppressed, liver tumors form and grow in chronic hepatitis mice .

In addition, among the 15 mice lacking anti-tumor cytotoxic T cells, 27% of the mice developed large liver tumors at 6 months, and none of the mice with cytotoxic T cells had tumors. There is almost no tumor in mice without immunosuppressive lymphocytes, suggesting the absence of IgA + cells, so that cytotoxic T cells can be let go to complete the anti-tumor effect.

PD-L1 has the effect of inducing immunosuppressive lymphocytes to suppress cytotoxic T cells, exposing the weakness of this mechanism of action. When the researchers used drugs or genetic engineering to inhibit PD-L1, IgA + cells were eliminated from the liver. Reactivated toxic T cells play a role in eliminating tumors. This provides theoretical support for blocking PD-L1 with PD-1 inhibitor drugs that can cause liver cancer regression. The first member of this class of drugs, nivolumab, has recently been approved for the treatment of advanced hepatocellular carcinoma. Researchers are studying how IgA + cells are aggregated into the liver, hoping to find ways to interfere with the accumulation or generation of these cells, and provide new ideas for the prevention or early treatment of liver cancer.

Bristol-Myers Squibb’s nivolumab (Nivolumab, Opdivo) was approved by the US FDA in September this year for hepatocellular carcinoma patients after sorafenib treatment, becoming the first and only FDA approved in this indication Of anti-tumor immune drugs.

At present, PD-1 inhibitors including Pembrolizumab (Keytruda), AstraZeneca’s Durvalumab (Imfinzi), BeiGene BGB-A317, Hengrui’s SHR-1210, etc. Clinical trials for liver cancer treatment are in progress.

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