Study Identifies Potential Trigger to Cancer-inducing Chronic Inflammation


Blocking the interaction between interleukin-33 and regulatory T cells may serve as a new therapeutic target for cancers associated with chronic inflammatory diseases.

New research has identified an interaction between immune factors that may trigger chronic, cancer-promoting inflammation, according to a new report published in PNAS.

Chronic inflammatory diseases account for up to 20% of all cancer deaths worldwide, according to the report. For the study, investigators aimed to identify the mechanism that initiates the development of a cancer-promoting immune environment in chronic inflammation.

In the report, the study authors found that elevated levels of the immune factor interleukin (IL)-33 and regulatory T cells (Tregs) may lead to the development of skin cancer associated with chronic dermatitis and colorectal cancer in patients with colitis. Using mouse models of chronic skin and colon inflammation and human samples, the investigators observed a dependency of tumor-promoting immune environments on the interaction between IL-33 and Tregs.

After regularly applying an irritating substance to the skin of mice, they saw an increase in IL-33 expression immediately before the transition from acute to chronic dermatitis and determined that IL-33’s presence was necessary for the transformation. The investigators noted that blocking the expression of IL-33’s receptor molecule on Tregs cells was found to prevent the development of skin cancer in animals with chronic dermatitis. Increases in both IL-33 and Tregs were also found in skin samples from patients with chronic inflammatory skin diseases and those with inflammation-associated skin cancers, according to the findings.

“Our research has revealed a critical immunological axis that initiates the development of cancer-promoting chronic inflammation,” senior author Shawn Demehri, MD, PhD, of the Massachusetts General Hospital Center for Cancer Immunology and the Cutaneous Biology Research Center, said in a press release about the findings. “This axis is chronic inflammation’s ‘Achilles heel,’ and blocking it promises to prevent cancer development in chronic inflammation, which accounts for almost 20% of all human cancer deaths worldwide.”

Additionally, IL-33’s direct signaling onto Tregs was also required for chronic colitis and its associated colorectal cancer development. The models showed that significantly increased IL-33 and Tregs marked the perilesional skin and colon in patients with cancer-prone chronic inflammatory diseases.

The findings suggest the role of the IL-33/Treg axis as potential therapeutic targets for cancer prevention and treatment in high-risk patients, the investigators concluded.

“Now we need to determine the efficacy of IL-33/Treg blockade for preventing cancer in patients and to test the role of that blockade in cancer treatments more broadly,” Dr Demehri said. “We’re hopeful that our findings will help reduce the risk of cancer for patients with chronic inflammatory diseases worldwide.”


Ameri AH, Tuchayi SM, Zaalberg A, et al. IL-33/regulatory T cell axis triggers the development of a tumor-promoting immune environment in chronic inflammation. PNAS. 2019.

Interaction between immune factors triggers cancer-promoting chronic inflammation [news release]. Massachusetts General Hospital. Accessed February 11, 2019.

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