How highly aggressive colon cancer evades the immune system
Researchers from the German Cancer Research Center (DKFZ) and the HI-STEM Stem Cell Institute have identified a previously unknown mechanism by which a particularly aggressive form of colon cancer evades the immune system.
Researchers from the German Cancer Research Center and the HI-STEM Stem Cell Institute have uncovered a novel mechanism by which aggressive colon cancer evades the immune system. Their study, published in Gastroenterology, reveals that activating a signaling pathway called WNT allows cancer cells to suppress the immune system, contributing to tumor growth.
Each year, around 55,000 people in Germany are diagnosed with colorectal cancer, with about a quarter of these cases stemming from a specific type of polyp called serrated lesions. These lesions, often carrying a BRAF gene mutation, produce particularly aggressive tumors that are resistant to current treatments. The molecular processes driving this aggressive subtype of colorectal cancer have remained largely unclear until now.
Led by René Jackstadt, the research team demonstrated that WNT pathway activation triggers malignant transformation and ultimately leads to tumor development. Using genetically modified mice, organoid models, and single-cell analyses, they investigated how WNT activation impacts the tumor microenvironment. They observed a significant remodeling of the tumor microenvironment, particularly focusing on the signaling molecule CCL20, which attracts immune cells.
However, they found that WNT-activated tumor cells produce significantly less CCL20, resulting in fewer immune cells infiltrating the tumor and enabling cancer cells to evade the body's immune defenses. In experimental models, restoring CCL20 production significantly slowed tumor growth.
This finding explains how BRAF-mutated colorectal tumors can evade the immune system and highlights the WNT signaling pathway as a potential target for future treatment strategies. While WNT inhibitors are already in clinical development, none have been approved for cancer treatment. Combining WNT pathway inhibition with immunological approaches could be promising, but further preclinical and clinical studies are needed to determine their efficacy in clinical practice.
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