A study shows that LKB1 deficiency in T cells increases gastrointestinal polyposis development.
The pro-inflammatory effects of germline deletion mutations in the tumor suppressor gene STK11 on immune T cells are sufficient to cause the cancer predisposition syndrome Peutz-Jeghers syndrome (PJS) in mice, researchers reported in Science.
The findings challenge the longstanding assumption that PJS patients’ polyps develop in lockstep with polyp cell–specific tumor suppressor gene expression, instead implicating mutations in immune T cells and resulting in immune-mediated inflammation.
“Our findings establish immune-mediated inflammation as a hallmark of PJS disease and highlight a critical role for STK11-mutant T cells in PJS disease progression,” reported senior study author Russell G. Jones, PhD, of the Goodman Cancer Research Centre at McGill University in Montreal, and coauthors.
In humans, PJS is an autosomal-dominant hereditary syndrome characterized by hamartomatous gastrointestinal polyps and an elevated risk of colorectal, stomach, pancreatic, lung, breast, gynecologic, and testicular cancers. In experiments with mice, the authors identified ways to target inflammatory signaling to slow STK11 mutation–associated polyp growth.
“Our results identify LKB1-mediated inflammation as a tissue-extrinsic regulator of intestinal polyposis in PJS, suggesting possible therapeutic approaches by targeting deregulated inflammation in this disease,” the researchers reported.
STK11 encodes LKB1. LKB1 is a serine/threonine kinase involved in glucose homeostasis and cellular metabolism, proliferation, and growth. Somatic STK11 mutations are also found in lung and gynecologic cancers, often alongside KRAS mutations, among non-PJS patients, the authors noted.
As with human patients with PJS, mice with heterozygous STK11 deletion mutations developed gastrointestinal polyps characterized by inflammatory T-cell infiltration, STAT3 signaling activation, and elevated inflammatory cytokine levels (interleukin [IL]-6, IL-11, and CXCL2), the researchers found.
Polyp sizes were significantly smaller in mice with heterozygous STK11 mutations, both in the absence of IL-6 expression and with lymphocyte deficiency.
Disrupting upregulated STAT3 signaling, IL-6 levels, or T-cell infiltration diminished polyp growth in STK11-mutated mice. Inhibiting STAT3 signaling with the JAK2 inhibitor AZD1480 was associated with significantly smaller polyps than those found in the controls, and reduced immune cell infiltration.
“Thus, the blockade of STAT3 signaling can affect polyp development in this PJS mouse model,” the authors concluded. “Our data argue for a more complex role for STK11 mutations in PJS disease development, with deregulated inflammatory responses by LKB1-mutant immune cells, in addition to epithelial and stromal tissues, reinforcing tumor inflammation and chronic STAT3 activation to drive polyp growth. Consistent with this, elevated IL-6 levels have been observed in LKB1-deficient tumors.”
The findings also suggest that gut infection interactions with heterozygous STK11 on immune cells could trigger PJS polyp formation, they noted. “Targeting chronic gastrointestinal inflammation may present a novel approach to reducing disease incidence and polyp burden in PJS patients,” the authors concluded.
Several investigational drugs are in development to target STK11 for cancer treatment, including metformin, used to treat type 2 diabetes.