Chronic stress helps tumors evade immune attack through gut microbes

Chronic psychological stress can help tumors evade immune attack through a chain of molecular events involving gut bacteria and viruses within those bacteria, according to a study led by Weill Cornell Medicine investigators. The findings unveil a new layer of cancer biology along with potential therapeutic opportunities.

In mice under chronic unpredictable mild stress, the anti-tumor B cell response (white) is suppressed. Credit: Zeng Lab

In the preclinical study, published June 25 in Cancer Cell, the researchers discovered that chronic stress causes some gut bacteria to escape from the gut and migrate to tumors. Viruses within these bacteria induce cells called cancer-associated fibroblasts (CAFs) within tumors to produce high levels of stress hormones, which in turn suppress local antitumor immunity. The researchers found evidence of this tumor-protecting mechanism in mouse models of cancer and in human cancer samples and showed that it can be thwarted by blocking a key receptor on CAFs.

Cancer patients typically experience high levels of stress chronically. However, it is unclear how perturbation of the gut microbiota by chronic stress impacts the response of the immune system to cancer. Our findings open up many new research directions, with possibilities for new treatments and prognostic tests for cancer patients."

Dr. Melody Zeng, study senior author, associate professor of immunology in pediatrics and member of the Gale and Ira Drukier Institute for Children's Health and the Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine

The study's first author is Dr. Hilal Bashir, a postdoctoral associate in the Zeng Lab. Other WCM faculty, including Drs. Gregory Sonnenberg, David Lyden, Irina Matei and Patrick Wilson, also contributed to this work.

Early in the study, the researchers found evidence from mouse models and human tumor samples that chronic stress impairs local antitumor immunity by raising levels of glucocorticoid stress hormones. Curiously, although stress hormone production in mammals occurs mainly in the adrenal glands atop the kidneys, the source of the stress hormones in these experiments seemed to be within the tumors—the levels were higher inside the tumors than in adjacent tissues.

The scientists also observed that this stress effect in mice was greatly reduced in germ-free mice or when the animals were dosed with broad-spectrum antibiotics to kill their gut bacteria, suggesting that the effect somehow requires these bacteria.

Ultimately the researchers uncovered a long and surprising chain of events underlying this effect: First, chronic stress triggers the usual adrenal-gland production of stress hormones, which raises levels of those glucocorticoids in the gut, activating glucocorticoid receptors on gut-lining cells. This weakens the lining of the gut, allowing specific gut bacteria to escape into the bloodstream—then into other tissues, including tumors if present. In the researchers' mouse models, the bacterial species Enterococcus gallinarum (Eg) dominated this gut-to-tumor microbial migration.

Bacterial cells can harbor small viruses called phages, and the team found evidence that these often burst from E. gallinarum inside tumors. The DNA in the phages then activates the DNA-sensing receptor called TLR9 on CAFs. TLR9 activation on fibroblasts causes the cells to start producing stress hormones, which suppress the part of the immune system that depends on antibody-making B cells—normally a significant arm of antitumor immunity.

The team found evidence of this process in samples of human colorectal tumors - a phage-laden gut bacterium Klebsiella pneumoniae isolated from human colon tumors was found to accelerate tumor growth significantly in mice. An analysis of microbial genomic data from human brain tumor samples suggested the presence of a different gut-dwelling bacterium, Enterococcus faecium, plus associated phages.

"I wouldn't be surprised to see multiple gut bacterial species involved in this process, particularly the species that are more adaptable to tissue environments outside the gut," Dr. Zeng said.

The researchers demonstrated that they could prevent this immune-suppressing cascade in mouse models with a compound that blocks TLR9 signaling, or even by injecting an antibiotic into tumors to kill tumor-resident bacteria.

Dr. Zeng said that her team currently is studying which therapeutic approach is likely to work best against this process, and whether the detection of phages in tumors could have prognostic value.

"These findings also underscore the importance of stress management in cancer and raise questions about existing therapeutic approaches that sometimes involve giving patients glucocorticoids," Dr. Bashir said.