The mechanism early cancer cells employ to evade the immune system

SOX17, active in embryonic development, influences intestinal and blood vessel development. Inhibiting SOX17 or its pathway may offer a new strategy to treat early-stage colon cancer before it progresses. Over time these large tumor cells can accumulate mutations, forming polyps that may evolve into metastatic colon cancer.

“Activation of the SOX17 program in the earliest innings of colorectal cancer formation is a critical step that shields precancerous cells from the immune system. If we can inhibit the SOX17 program, we might be better able to prevent colon cancer, particularly in patients that are prone to developing colon polyps,” says Omer Yilmaz, an MIT associate professor of biology, a member of MIT’s Koch Institute for Integrative Cancer Research, and one of the senior authors of the study.

To understand how precancerous growths avoid immune detection, researchers employed a method to cultivate mini colon tumours in a laboratory dish, subsequently implanting them into mice. These tumours were engineered to carry mutated forms of the cancer-associated genes Kras, p53, and APC, commonly found in human colon cancers. Upon implantation in mice, researchers noted a significant upregulation of SOX17 expression within the tumours.

The findings revealed that when SOX17 is activated in cancer cells, it fosters an immunosuppressive environment by inhibiting the synthesis of interferon-gamma receptors, crucial for the immune response against cancer. This prevents cells from neglecting signals for programmed cell death, evading immune attack.

“One of SOX17’s main roles is to turn off the interferon-gamma signalling pathway in colorectal cancer cells and in precancerous adenoma cells. By turning off interferon-gamma receptor signalling in the tumour cells, the tumour cells become hidden from T cells and can grow in the presence of an immune system,” Yilmaz says.

In the absence of interferon-gamma signalling, cancer cells reduce MHC protein production, impeding the display of cancerous antigens to the immune system, and hinder the production of chemokines, which recruit T cells to eliminate the cancerous cells.

Reference: Pelka, K. et al. Spatially organized multicellular immune hubs in human colorectal cancer. Cell DOI: 10.1038/s41586-024-07135-3