MUSC Hollings Cancer Center researchers discovered a new mechanism that shows how a particular gene mutation can allow tumors to evade detection by the immune system in colorectal cancer patients. The study, published July 22 in Oncogene, is the most recent example of team science at Hollings.
“It’s the first time we know of anyone showing how a checkpoint inhibitor is regulated as a result of loss of adenomatous polyposis coli (APC) gene function,” he said. Raymond N. DuBois, MD, Ph.D., director of Hollings Cancer Center and a senior author of the study.
🎬📺 Free Movies and Free TV Shows! 🎭🎬
Colorectal cancer is the third most common malignancy and the second leading cause of cancer death in the United States. Although colonoscopy screening is an effective way to detect and prevent colorectal cancer by removing polyps, colorectal cancer continues to be responsible for significant mortality. DuBois said existing therapies have limited efficacy for long-term survival in patients with stage 4 disease.
“The five-year survival rate for these patients is unacceptable, between 5% and 15%, underlining the importance of this research,” said DuBois.
The DuBois lab team has been working to understand the molecular mechanisms driving colorectal cancer initiation, growth and progression to discover new strategies for prevention and interception.
The immune response to cancer is regulated by a balance between costimulatory and inhibitory (checkpoint) pathways. Immune checkpoints inhibit the immune system and prevent inflammatory tissue damage and autoimmune diseases. For example, an immune checkpoint pathway is activated by PD-L1, an immune system regulatory molecule that suppresses immune responses when it interacts with its receptor, PD-1.
“PD-L1 levels are elevated in a variety of human cancers, including colorectal cancer, and this sometimes leads to a poor prognosis,” DuBois said. “We know that high levels of PD-L1 on the surface of cancer cells are related to the tumor’s ability to evade the immune system. However, the exact role that PD-L1 plays in colorectal cancer is unclear. Some reports in the literature present conflicting results as to whether the presence of PD-L1 is indicative of a better or worse cancer prognosis.”
The immune system and how to bypass it?
T cells, crucial white blood cells that help mediate the immune system, can kill cancer cells or virally infected cells. Tumor cells must therefore evade them if they want to survive by directly reducing the cytotoxic activity of T cells. Tumor cells also inhibit T cell proliferation by using immune checkpoint receptors such as PD-1. PD-1 and PD-L1 work together to inhibit T cell function while increasing immunosuppression by regulatory T cells (Tregs). As this complex dance of T cells, checkpoint receptors and Tregs takes place, tumor cells slip by and evade the immune system.
The APC Mutation Connection
Normally people have two copies of the APC gene, which they have inherited from their parents. The APC gene provides instructions for making the APC protein, which helps determine how often a cell divides and how it attaches to other cells in a tissue. The APC protein thus acts as a tumor suppressor and prevents uncontrolled growth and division of cells. If one copy of the APC gene has a mutation, there is an increased risk of developing certain types of cancer, such as colorectal cancer and other cancers of the stomach, thyroid, pancreas, liver and central nervous system.
Previous animal studies provided direct evidence showing that the loss of APC causes the formation of adenomas, which are noncancerous tumors that can become cancerous over time. The APC protein can form a complex with -catenin, which plays an essential role in stem cell renewal and organ regeneration. DuBois’s team conducted several experiments that showed that β-catenin is required for APC mutation and increased levels of PD-L1.
DuBois’s team found that in mouse models, APC gene mutations are always accompanied by very high levels of PD-L1. With that knowledge, they developed various mouse models in which they deleted the gene and examined its effect on the large intestine.
This discovery represents the first evidence known to show that the loss of APC results in stimulation of PD-L1 in colon cancer cells via the b-catenin complex that binds to the PD-L1 promoter.
— Dr. Raymond N. DuBois
“When we corrected the mutation in the mouse model, the checkpoint inhibitor disappeared and when we reintroduced the mutation, it returned,” explains DuBois.
“This discovery represents” the first evidence known to show that the loss of APC results in stimulation of PD-L1 in colon cancer cells through the Bcatenin complex that binds to the PD-L1 promoter,” said DuBois.
Their findings also revealed a novel mechanism by which APC mutations enable colon tumors to evade immune detection through an immune checkpoint pathway and increased resistance to T cells. “These results advance our understanding of the role of APC in colorectal cancer and pave the way for the development of new target drugs B-catenin inhibitors for use as alternative immune checkpoint inhibitors in colorectal cancer therapiesDuBois said. These new therapies may be especially helpful in intercepting the progression of colorectal cancer disease at a very early stage.
The DuBois laboratory plans to investigate the effectiveness of the combined use of checkpoint inhibitors with existing therapies, such as small-molecule drugs. He hopes this discovery will encourage related research by other institutions and ultimately explain why colorectal cancer patients typically do not respond well to immunotherapy.
“We know that there are other pro-inflammatory pathways that inhibit the immune system’s ability to attack tumor cells that are different from the immune checkpoint pathway. We’re using animal models to test compounds that can block those inflammatory pathways. Now we’re using those in addition to checkpoint inhibitors, and the combination of both approaches could prove to be a groundbreaking and effective new therapy.”