Colorectal cancer is one of the most common forms of cancer and, as the second-leading cause of cancer deaths, it is also one of the most serious. For years, cancer researchers have been searching for ways to prevent and treat colorectal cancer more effectively.
A recent study by the Medical University of South Carolina (MUSC) Cancer Center may have discovered a way to reach this goal through a new technique designed to help the immune system fight the disease more effectively.
Findings on PD-1 Proteins and Pathways
Cancer cells often spread throughout the body, or metastasize, by evading the immune system’s natural defenses. The immune system naturally fights mutated cells by killing cancerous cells with cytotoxic CD8+ T-cells and then disposing of cellular debris using phagocytic macrophages. But unfortunately, this process does not always work. Cancer cells often circumnavigate these natural defense systems.
A protein called PD-1 has been found to negatively affect the response of the immune system. The processes behind PD-1’s effects on the immune system are currently not well understood by researchers.
The MUSC researchers used mouse models of colorectal cancer and complicated genetic techniques to identify a specific pathway responsible for CRC immune system evasion: EP4-PI3K-NFkB-PD-1.
The immune system releases prostaglandins, fatty molecules similar to hormones, in response to inflammation. The team discovered a novel role of a prostaglandin called PGE2 in tumor immune evasion. PGE2 is the most common prostaglandin found in cancers, and high levels of it are correlated with poor expected outcomes for cancer patients.
The researchers found that PGE2 triggers PD-1 expression through a sequence of intermediary pathways. This effect impairs the ability that CD8+ T-cells and macrophages have to attack developing cancer cells.
Blocking the EP4 Molecule
In the next step of this study, researchers discovered that blocking the EP4 molecule could act as an aid to the immune system, allowing it to fight cancer more effectively. The researchers blocked EP4 in a mouse model of colorectal cancer and found that using a receptor inhibitor allowed the immune system to recover the CD8+ T-cell cytotoxicity.
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This process essentially interrupts the pathway that was causing immune evasion of colorectal cancer by reducing PD-1 levels in CD8+ T-cells and macrophages, leading to more effective anti-cancer mechanisms in the intestines. The researchers believe these findings show that the negative effect of high PD-1 levels on cancer outcomes can be reversed by using EP4 inhibitors. Additionally, these inhibitors could potentially be used in tandem with checkpoint inhibitors to treat patients with more advanced cancers.
How EP4 Inhibitors Could Be Used to Prevent Cancer
Cancer treatment was the primary focus of this study, but the researchers believe that the EP4 inhibitor could also be used to prevent the disease. Individuals with a high risk of cancer are often advised to take aspirin, which has been found to delay the onset of cancer. However, aspirin can be detrimental to the gastrointestinal system. If the study’s findings on EP4 prove to be accurate, it could be used as an alternative to aspirin.
The Importance of Studying Early Stage Colorectal Cancer
The findings of this study are exciting because much of the past research on inhibitors as a form of colorectal cancer treatment have yielded discouraging results. While checkpoint inhibitors and other immunotherapies have shown promise in the treatment of some forms of cancer, they have proven ineffective when tested on colorectal tumors.
Scientists have studied how several molecular pathways could be used to identify new drug targets. However, the majority of this research has been conducted on patients with late-stage colorectal cancer that has metastasized.
The scientists at MUSC believe that studying the interactions between cancer and immune cells in the early stages could provide additional answers, as researchers currently know very little about the inner workings of the immune system during the premalignant stage of cancer development.
Previous Colorectal Cancer Study by MUSC Hollings Cancer Center
The most recent study built off the findings of a previous study published by DuBois in July 2021. This study found that a checkpoint inhibitor was regulated because of the loss of the adenomatous polyposis coli (APC) gene function. Most people have two copies of this gene, one inherited from each parent. This gene contains a blueprint for the APC protein, which controls the frequency of cell division and how cells attach to other cells within the same tissue.
The APC protein serves as a tumor suppressor, preventing it from growing uncontrollably. But if someone has one mutated APC protein, they are at a higher risk of developing colorectal cancer and other types of cancer. Researchers found that APC mutations allow tumors to evade detection by the immune system through an immune checkpoint pathway.
MUSC Hollings believes that the most recent study builds off the findings of the July study, providing the oncology research community with additional valuable information that could be used in the search for more effective cancer treatments and prevention methods.