Biopsies of the colon in individuals with inflammatory bowel disease (IBD) who later develop cancer consistently reveal a striking and unexpected finding. Neutrophils, the white blood cells typically dispatched to combat infections, congregate densely around early tumor cells within tissues where their presence is unwarranted.
The origin and driving force behind this substantial infiltration of neutrophils have remained one of the area’s most perplexing and unresolved questions. However, a novel study has now demonstrated that the signal originates directly from the bone marrow, which was responding to directives from the inflamed gut. These research findings have been published in the journal Immunity.
The investigation commenced with an examination of a protein known as TL1A, which is present in the inflamed intestines of individuals suffering from IBD.
Researchers were already aware of TL1A’s association with disease flares and tumor progression. Nevertheless, the precise mechanism by which it bridges these two processes remained elusive. Pharmaceutical companies had been endeavoring to target TL1A for years.
Currently, three companies have antibodies in clinical trials for treating Crohn’s disease and ulcerative colitis, with early results showing promise. It’s important to note that none of these efforts were initially aimed at combating cancer.
The research was spearheaded by Randy Longman, a gastroenterologist who leads the Jill Roberts Center for Inflammatory Bowel Disease at Weill Cornell Medicine. His team engineered mice with either an active or inactive TL1A signaling pathway, induced intestinal inflammation in both groups, and observed tumor development exclusively in the mice with active TL1A signaling.
Within the inflamed colon, TL1A exerted its influence on a specific subset of immune cells residing in the intestinal wall. Upon activation, these cells released a chemical signal that traveled through the bloodstream to the bone marrow, instructing it to ramp up the production of neutrophils.
This directive triggered a sort of manufacturing crisis. The newly produced white blood cells then flooded out of the bone marrow, heading directly toward the colon.
While earlier studies had identified various immune cells involved in IBD-associated cancer, the precise pathway of this communication from the gut to the bone marrow remained unclear, according to a 2021 review.
Establishing the link between the chemical signal and the bone marrow’s response effectively connected two biological components that researchers had largely studied in isolation.
Neutrophils are typically the first responders to infection. They work to eliminate bacteria, clear damaged tissue, and otherwise remain in limited numbers. A biopsy of a healthy colon would not reveal them in significant quantities.
However, in mice with the TL1A gene mutated, the colon biopsies presented a vastly different picture. Neutrophils were found tightly packed against the lining and clustered around nascent tumor sites. Mice lacking TL1A signaling did show some neutrophil recruitment, but in far reduced numbers, and their bone marrow never sent out the alarm signal.
This was apparently not mere chance. The neutrophils were not only more numerous; they seemed to be inflicting damage that, over time, set the stage for tumor development.
These intestinal immune cells were not merely summoning neutrophils. It appeared they were also reprogramming them. Each neutrophil arrived in the colon with an altered gene activity pattern, including genes previously shown in other studies to be implicated in tumor initiation and growth.
Prior to this research, no one had identified this intermediate step. It was known that neutrophils release reactive molecules capable of damaging DNA in neighboring intestinal cells.
What was novel was the discovery that they could arrive already pre-programmed to support tumor progression. To ascertain if neutrophils alone could drive this effect, the team introduced additional neutrophils into mice that already had intestinal tumors.
The outcome was accelerated cancer cell growth, reinforcing the connection between TL1A and tumor advancement. The researchers also examined biopsy samples from 12 IBD patients, including nine with dysplasia – a precancerous change in colon cells – and three without.
The neutrophil pattern was evident only in the group with dysplasia. Some of these patients had undergone experimental treatment that blocked TL1A. Their tissue samples showed reduced activity in a gene known to promote tumor development. This human data mirrored the findings from the mouse studies.
Silvia Pires, the study’s lead author from Longman’s lab, noted that this gut-bone marrow communication suggests IBD should be viewed as a systemic illness, not one confined solely to the intestines. Such a broader perspective could pave the way for more targeted therapeutic strategies. This revelation aligns with an already emerging pharmaceutical landscape.
Several companies are in the later stages of clinical trials with TL1A-blocking antibodies for IBD treatment, and one Phase 2b trial has been expanded to include other inflammatory conditions.
These drugs were developed to quell inflammation, not to prevent cancer. However, the new findings suggest they may serve both purposes. Inhibiting TL1A could disrupt the “gut-bone marrow” axis, including the pathway that draws pro-tumorigenic cells to the colon. Existing IBD medications do not offer this dual benefit.
Biologics and immunosuppressants alleviate symptoms but do not directly alter the trajectory towards cancer. Patients still rely on colonoscopies to detect tumors once they have formed.
The link between inflammation and colon cancer has been recognized for nearly 80 years, dating back to a 1949 publication concerning chronic ulcerative colitis and its associated carcinoma.
Researchers had largely described this association in broad terms, pointing to mechanisms such as DNA damage, compromised intestinal barrier function, and microbial dysbiosis.
The current work, however, identifies the specific cells, signal, and damaging white blood cells involved. Clinical trials for TL1A blockers can now incorporate endpoints related to colorectal cancer, alongside symptom assessments.
Patients experiencing recurrent flares that trigger an emergency response in their bone marrow should be flagged for closer monitoring.
Longman’s research team is now investigating whether earlier, less pronounced exposures to the same chemical signal might prime the bone marrow for IBD and if preventive interventions could be initiated much sooner.
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