Researchers find new target for intestinal cancer in microbiome

Researchers from the Medical University of Vienna recently identified an unknown mechanism that triggers colorectal cancer (CRC), as detailed in results from a preclinical study published in Communications Biology. They believe this mechanism offers a new therapeutic target. 

The mechanism is centered on Paneth cells, which are a type of glandular cells that facilitate the division and self-renewal of stem cells in the gastrointestinal tract. Paneth cells are also found in human colorectal cancer polyps, with frequencies of 0.2% to 39%. The researchers discovered that Paneth cells, which produce the enzyme IDO1 (indoleamine-2,3-dioxygenase-1), suppress the immune system from fighting against intestinal cancer in the stem cell area of intestinal crypts and tumors.

“According to our hypothesis, the bacterial microbiome induces the IDO1 immune checkpoint in the Paneth cells, thereby preventing local intestinal inflammation,” stated lead author Robert Eferl, PhD. “However, this also gives rise to immunosuppressed areas, in which intestinal tumors can develop. IDO1-expressing Paneth cells are therefore a cellular target for immune-based therapies.”

Paneth cells and tumor growth

Sensitizing cancer cells for an immune attack is an important strategy for ensuring the success of immunotherapy treatment. However, not much is known about the underlying mechanisms that allow cancer to escape the immune system.

In this study, the team used an ApcMin mouse model in which they had knocked-out the transcription factor Stat1 in intestinal epithelial cells. They used this model because mutations in the Apc gene lead to intestinal cancer. The team found that loss of Paneth cells in Stat1-deficient intestinal tumors led to decreased tumor burden and higher infiltration of anti-tumor immune cells, including cytotoxic T lymphocytes. 

Upon further investigation, the team identified a subset of Paneth cells that exhibited reduced Stat1-dependent expression of IDO1. Of note, IDO1 translates an enzyme that yields the metabolite kynurenine, which suppresses tumor immune response, thus bolstering tumor growth at the level of intestinal crypts and tumors.

According to prior research by other investigators, intestinal tumors from patients with familial adenomatous polyposis with inherited Apc mutations demonstrated tumor cell content that was greater than 90% Paneth cells. Although the exact role of these cells in tumor formation remains to be elucidated, CRC usually develops in colonic mucosal tissue replete with Paneth cell metaplasia. Furthermore, the incidence of Paneth cell-containing adenomas heightens the odds of synchronous CRC. In other words, Paneth cells likely promote the development of CRC. 

Improving immunotherapy

The authors highlighted the potential role of the microbiome in tumor formation. “Stat1-dependent IDO1+ Paneth cells were also found in normal murine crypts. They did not depend on ApcMin but the presence of the Min mutation affected their spatial distribution in the distal small intestine and colon,” they wrote.

”Extra clean SPF [special pathogen-free] conditions and treatment of mice with antibiotics substantially reduced the number of IDO1+ crypts in all parts of the intestine,” they continued. “Moreover, IDO1+ Paneth cells in normal crypts were enriched in the distal small intestine, which has a high bacterial load, and we could identify Ido1 induction in Paneth cells of bacteria-infected mice using scRNA-seq data. This suggests that IDO1+ Paneth cells are induced by the local microbiome.”

The researchers noted that IDO1+ Paneth cells could provide safe harbor for tumor growth in the form of immune-privileged niches for tumor formation. New adenomas could take advantage of these niches to avoid anti-tumor immune onslaught during the elimination and equilibrium phases of immunoediting. 

“Consistent with this idea, neoplastic IDO1+ Paneth cells were particularly abundant in early adenomas of ApcMin mice,” the researchers wrote. “Of note, tumor formation was impaired in ApcMin mice kept under germ-free conditions.” 

They concluded: “Targeting IDO1+ Paneth cells might improve efficacy of immunotherapy in microsatellite-stable CRC patients. Besides representing a conceptual advance, our findings will improve precision oncology of CRC.”