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Your Environment. Your Health.

New Tumor-Promoting Pathway for Liver Cancer Discovered

Ronald Evans, Ph.D., Michael Karin, Ph.D.
University of California San Diego School of Medicine
P42ES010337

A new study from NIEHS grantees showed that chronic liver inflammation can promote cancer by suppressing one of the body’s natural mechanisms to fight cancer development. The discovery of this new tumor-promoting pathway could lead to new liver cancer treatments.

The researchers studied a new mouse model of liver cancer that more closely mimics the way that human liver cancer develops. In these mice, tumors develop as a natural consequence of non-alcoholic steatohepatitis (NASH), a chronic metabolic disorder that causes liver damage, fibrosis, and cell mutations.

The researchers found that mutations associated with NASH provoke cytotoxic T cells to recognize and attack the newly emerging cancer cells. However, chronic liver inflammation led to the accumulation of another type of immune cell known as immunosuppressive lymphocytes. The experiments showed that immunosuppressive lymphocytes use a molecule known as PD-L1 to interfere with cytotoxic T cells, leading to liver tumors in the chronically inflamed mice. In mice lacking tumor-fighting cytotoxic T cells, 27 percent of 15 mice had large liver tumors at six months. However, mice of the same age that retained their cytotoxic T cells had no tumors. Similarly, mice without immunosuppressive lymphocytes had almost no tumors even at 11 months, most likely because cytotoxic T cells could fight the emerging cancer.

The results could help scientists develop new ways to interfere with immunosuppressive lymphocytes to prevent or treat early liver cancer.

Citation: Shalapour S, Lin XJ, Bastian IN, Brain J, Burt AD, Aksenov AA, Vrbanac AF, Li W, Perkins A, Matsutani T, Zhong Z, Dhar D, Navas-Molina JA, Xu J, Loomba R, Downes M, Yu RT, Evans RM, Dorrestein PC, Knight R, Benner C, Anstee QM, Karin M. 2017. Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity. Nature 551(7680):340-345.