T-Cell Mutation Leads to GI Polyps

Peutz–Jeghers syndrome (PJS), a cancer predisposition syndrome characterized by benign gastrointestinal (GI) polyps, results from a germline mutation in STK11, the gene that encodes the tumor suppressor LKB1. A recent study provides a possible mechanism: A single-allele mutation of STK11 reduces LKB1 expression in T cells, increasing production of inflammatory immune cells in the GI tract that promote the growth of these polyps (Science 2018;361:406–11).

Previously, senior author Russell Jones, PhD, of McGill University in Montreal, Canada, and the Van Andel Institute in Grand Rapids, MI, and his team established that the absence of LKB1 in T cells increased T-cell activation and the production of inflammatory cytokines (J Immunol 2011;187:4187–98). Building on this work, the new study aimed to determine whether this inflammatory response could lead to the development of autoimmune diseases.

However, the study direction changed when the researchers unexpectedly discovered that mice with single-allele deletion of STK11 in T cells developed GI polyps akin to those observed in PJS.

“It was previously believed that it's the mutation of STK11 in epithelial cells of the gut that causes the epithelial cells to grow abnormally, and that's why you get these tumors,” Jones says. “What ended up being the new focus of the study was tackling every angle of what the T cells could be doing, who they could be talking to, what factors they could be making that would be promoting tumor growth.”

The researchers found that polyps from mice and humans contained an inflammation signature that included T cells, macrophages, neutrophils, and the cytokines IL6 and IL11.

A series of follow-up experiments in mice established a likely mechanism for how STK11 deletion in T cells leads to PJS: First, a STK11 mutation reduces LKB1 production in T cells, which unleashes a storm of inflammatory factors that are recruited to the gastrointestinal tissue. Then, these inflammatory factors activate the JAK–STAT signaling pathway, increasing STAT3 production and creating an environment where polyps are likely to grow. The production of STAT3 is also known to drive tumor development in certain inflammatory cancers.

“What's interesting about this paper is that it shows that the partial loss of a tumor suppressor in one tissue, in this case LKB1 in T cells, has a very profound effect in promoting the growth of tumors in a different compartment of the body, the gastrointestinal tract,” says Pablo Hollstein, PhD, of the Salk Institute in La Jolla, CA, who coauthored a related commentary (Science 2018;361:332–3).

In the study, treating mice with a JAK2 inhibitor reduced polyp growth, suggesting that the JAK–STAT pathway has potential as a therapeutic target for controlling benign polyp growth in patients with PJS. He adds that “it will be of great interest to see if utilizing JAK inhibitors could help treat some of the malignancies that may occur down the road,” in patients with the syndrome, such as GI, pancreatic, and gynecologic cancers.

In a related study published earlier this year, lead author Saara Ollila, PhD, and senior author Tomi Mäkelä, MD, PhD, both of the University of Helsinki in Finland, found that LKB1 deficiency in stromal cells also leads to PJS via an inflammatory response that turns on the JAK–STAT pathway (J Clin Invest 2018;128:402–14).

“It seems that loss of LKB1 in different kinds of cell types can lead to similar types of responses,” Ollila says. “It's very important for the field that we ended up at the same conclusion: JAK–STAT signaling is at least one of the key pathways driving the growth of these [benign polyps].”

“What all of these studies are trying to understand is why patients with a heterozygous mutation of STK11 get polyps,” Mäkelä adds. “To me, the question is, ‘What is initiating the inflammatory response?’” –Catherine Caruso

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