The key to the development of colorectal carcinoma is creating an immunosuppressive environment

It is well-known that cancer can be triggered and advanced by interactions between immune cells and pre-cancerous cells. The dynamics of these interactions are not well understood. Researchers at Moffitt Cancer Center have shown that creating an immunosuppressive environment is crucial for the progression of benign colorectal cancers to invasive, malignant carcinomas. Nature Communications published their findings.

Colorectal Cancer is the third most prevalent cancer in the U.S. It is estimated that 1 in 25 Americans will be diagnosed with it during their lifetime. Despite the high incidence of colorectal cancer in America, it is on the decline. Better screening and diagnostics have allowed for the detection of pre-cancerous lesions before they become malignant carcinomas. Studies show that pre-cancerous lesions are not more likely to become cancerous than those with adenomas.

Bowel cancer screening programs identify approximately five high-risk adenomas per cancer discovered. Longitudinal endoscopic surveillance of the adenomas shows that less than 2% of them progress to cancer in three years. It appears that there is a significant evolutionary hurdle that must be overcome in order for an adenoma become invasive.

Sandy Anderson, co-founder of Moffitt’s Center of Excellence for Evolutionary Therapy at Moffitt, is the lead study author and chair of the Integrated Mathematical Oncology Department.

Anderson and his team included collaborators from Barts Cancer Institute in UK. Their goal was to increase their understanding of the hurdles pre-cancerous cancers must overcome before they can progress to invasive carcinomas. To characterize these events, they used spatial ecological analyses and mathematical modeling of patient tissues. Ecologists often use mathematical models to study interactions among species. They are ideal tools for analyzing complex interactions between human cells, which would otherwise be difficult to evaluate in standard laboratory studies using cell and mouse models.

The researchers focused their analysis upon interactions between immune cells with cancer cells, including the processes immune blockade (immune suppression), antigenicity, and immune blockade. The immune blockade process is when cells block the immune cells’ actions, such as T-cells. This causes inhibition of immune activity. To suppress an immune response, immune cells such as M2 macrophages from the surrounding area infiltrate the affected tissue. These immune cells can also produce factors which contribute to the growth of cancer cells. Antigenicity refers also to the presence of tumor-specific protein markers on tumor cells that immune cells can recognize. The immune cells then can target the tumor cells to be destroyed. Antigens are often mutated proteins that a tumor cell acquires, which contribute to tumor growth. Tumors carefully control the levels of antigens that are on their surfaces. While mutations are important for tumor progression and can lead to increased levels of antigens at the tumor surface as well as increased immune cell detection.

The researchers discovered that immune escape is a “bottleneck” through the which pre-cancerous tumors must progress to malignant carcinoma. This can be achieved most often by creating an immunosuppressive niche. Adenomas exhibit low levels of immune suppression, large infiltrates of cytotoxic cells, and a wide range of immunogenic antigens that are easily recognized by immune cells. These characteristics prevent adenomas becoming carcinomas. Adenomas which progress to a malignant stage create a niche that is rich in immunosuppressive cells, cytokines, and prevent the tumor being destroyed by predatory immunity cells. As the early malignant tumor progresses, the immune-suppressive cells and the cytokines levels increase. This allows the tumor to remain in an environment that is free from tumor-targeting immune cell. It can grow and acquire additional antigens to become fully malignant.

“As the immunosuppressive niche plays a fundamental role in progression and persistence, reengineering of the microenvironment towards an immuno-hot phenotype might prove to be an effective form immunotherapy,” stated Chandler Gatenbee (a research scientist in the Integrated Mathematical Oncology Department) and a member Anderson’s laboratory.