Researchers at the University of California San Diego (UCSD), funded in part by NIEHS, reported a new mechanism by which long-term liver inflammation promotes cancer. The study, published Nov. 8 in the journal Nature, explains the success of some types of cancer immunotherapy and suggests novel targets for new therapies.
Chronic inflammation is known to drive many cancers, especially liver cancer. Researchers have long thought that was because the effects of inflammation both stimulate cancer cells to divide and protect them from cell death.
In the new study, scientists found that in the liver, chronic inflammation also suppresses a natural defense mechanism known as immunosurveillance. This mechanism involves cells in the immune system, known as cytotoxic T cells, that guard against disease agents such as viruses, bacteria, and cancerous and precancerous cells.
The body’s guards may prevent cancer
“Recent successes in cancer immunotherapy ... demonstrate how activated immune cells can eradicate tumors, but until now we didn’t fully appreciate immunosurveillance or the role of adaptive immunity in tumor formation,” said senior author Michael Karin, Ph.D., a grantee in the NIEHS Superfund Research Program (SRP). Karin led the study with first author Shabnam Shalapour, Ph.D., an assistant professor in his group.
The adaptive immune system eliminates foreign pathogens and cancer cells from the body. “This study provides one of the strongest and most direct demonstrations that adaptive immunity actively prevents liver cancer,” Karin said.
“Research has associated liver cancer with pollutants commonly found at Superfund sites, including carbon tetrachloride, trichloroethlyene, nitrosamines, and arsenic,” said Michelle Heacock, Ph.D., from the NIEHS Hazardous Substances Research Branch. “This is an exciting finding, because understanding how inflammation interferes with the body’s cancer defenses clarifies the risks posed by these pollutants.”
New methods support discovery
The team used a new mouse model of liver cancer that more closely mimics human liver cancer associated with nonalcoholic steatohepatitis (NASH), which is a severe form of nonalcoholic fatty liver disease.
NASH, which is associated with obesity, is a chronic metabolic disorder that causes liver damage, fibrosis, and numerous cell mutations. Karin said that NASH is expected to soon become the leading cause of liver cancer in the U.S. and other Western countries.
Immune cells battle each other
The researchers found that the adaptive immune system, including cytotoxic T cells, recognized and attacked emerging cancer cells. They also found that in both mice and humans, chronic liver inflammation led to accumulation of cells called immunosuppressive lymphocytes. Karin and Shalapour first described these immune cells two years ago.
In the battle between these two types of cells, immunosuppressive lymphocytes won, by using a molecule known as PD-L1 to interfere with cytotoxic T cells. With the brake on T cells, liver tumors formed and grew. When the researchers inhibited PD-L1, either with a drug or by genetic engineering, cytotoxic T cells were re-invigorated and cleared the tumors.
New treatment targets
“These findings provide an explanation for the remarkable ability of so-called anti-PD-1 drugs, which block the receptor for PD-L1, to induce liver cancer regression,” Karin said. “The first member of this class of drugs was recently approved for the treatment of advanced liver cancer.”
Karin, Shalapour, and their team are now working out how immunosuppressive lymphocytes are recruited to the liver. Finding a way to interfere with the recruitment or generation of these cells may provide new means for liver cancer prevention or early treatment.
Shalapour S, Lin X-J, 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(plus) cells dismantle anti-liver cancer immunity. Nature 551(7680):340–345.
Shalapour S, Font-Burgada J, Di Caro G, Zhong Z, Sanchez-Lopez E, Dhar D, Willimsky G, Ammirante M, Strasner A, Hansel DE, Jamieson C, Kane CJ, Klatte T, Birner P, Kenner L, Karin M. 2015. Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy. Nature 521(7550):94–98.
Shalapour S, Karin M. 2015. Immunity, inflammation, and cancer: an eternal fight between good and evil. J Clin Invest 125(9):3347–3355.
(This story is based on a UCSD press release by Heather Buschman, Ph.D.)