FGL1 — the mastermind behind colon cancer
Key Terms:
FGL1 — a gene that encodes for proteins that reduce the infiltration of T-cells in the liver
CRC — Colorectal cancer
TAM — white blood cells that are found in the tumor environment and responsible for reacting to tumors (can be good or bad)
Lag-3/PD-1 — two immune checkpoint proteins that regulate the expression of T-cells
T-cells — immune cells that attack pathogens and abnormal cells
The Problem
CRC, also known as colorectal cancer, is the third most commonly diagnosed cancer and the second leading cause of cancer mortality globally. About 50% of colorectal cancer patients develop liver metastases, making CRC the major cause of death from cancer. On average, the 5 year survival rate is less than 20%. Unfortunately, this cancer is new to the field of research, and it was not until recently that researchers began experimenting on the biological processes that cause CRC. In the human body, the immune system has a way of targeting pathogens by the use of T-cells. However, the immune system also has a way of regulating these T-cells in order to stop them from targeting healthy cells. CRC exploits this regulatory system to go under the radar. On the bright side, researchers from China studied that CRC can be disrupted using a method called ICB, also known as immune checkpoint blockade.
Experiment
In the experiment, researchers found that FGL1 had suspiciously high expression in CRC. As they experimented, they found that FGL1 facilitated the progression of CRC cells by reducing anticancer immunity in the liver environment. Unfortunately, it was a little more complicated than one gene causing cancer to thrive. These researchers found that TAMS stabilized FGL1 by using NFkb, a pathway that decreased OTUD1 ubiquitination of FGL1 (ubiquitination is a process of degrading proteins). Moreover, it was found that FGL1 bonded to LAG-3, and PD-L1 T-cell receptors, which inactivated T-cells and inhibited the immune environment.
The Solution
With such a complex microenvironment within the liver, researchers were still able to find immunotherapy options against CRC despite the environment making research complicated. The combination of ICBs, such as anti-PD1 and antiCSD1R (disrupting TAM), stops FGL1 from binding to T-cell receptors. Researchers also experimented with combining benzethonium chloride, an inhibitor of tumor cell progression, and anti-PD1, which created a significant decrease in tumor growth and increased T-cell infiltration. Blockading LAG-3 was also found to enhance T-cell response.
Discussion
In conclusion, the study the researchers conducted was meant to understand the mechanistic connections between immune cells and tumor cells in the liver microenvironment. The study pinpoints FGL1, the mechanism that is exploited by cancer cells to create tumors. Even though no single solution was identified and brought into clinical trials, the researchers were still able to study a relatively new area of cancer research. The complicated liver microenvironment made research difficult, and it was incredible to see how researchers overcame this challenge. However, further research needs to be done. Researchers are continuing to find strategies and combinations of different therapies for liver cancer immunotherapy.
