Scar tissue drug dismantles cancer's defences to boost immunotherapy
Immunotherapy has emerged as a powerful tool in the fight against cancer, but there are still many ways for the disease to elude its advances. One trick cancer cells use to evade an attack is to shield themselves behind a particular type of healthy cell, and scientists at the University of Southampton have found a new way to intervene in this process using a drug originally developed to treat scar tissue.
By leveraging the body’s immune defenses and supercharging their ability to attack cancer, immunotherapy has brought a range of options to the table when it comes to cancer treatment. One way it does this is by ramping up the effectiveness immune cells called lymphocytes, by enhancing their ability to infiltrate tumors and take out malignant cells.
But a lot of the time lymphocytes don’t make it through, with the tumor able to repel its advances and continue to grow. The University of Southampton scientists have been investigating the reasons why this occurs and why a lot of patients fail to respond to immunotherapy, and now believe they have some answers.
The team conducted experiments on mice with lung and colon cancers, observing how cancer cells can hijack a normal type of cell called a fibroblast, using it as a shield to hide from the lymphocyte attack. In these cases, they become known as cancer-associated fibroblasts (CAFs), and scientists believe they play a pivotal role in preventing immunotherapy from working, with many solid cancers exhibiting a high concentration of these corrupted cells.
An enzyme called NOX4 was found through previous research to be key to the formation of CAFs, so the team set out to explore how they might inhibit its activity. In the mice experiments, the team blocked NOX4 both through genetic engineering and a drug called Setanaxib, which is currently being trialed clinically to treat the scarring of organ tissue.
The team found that this approach served to prevent or even reverse the formation of CAFs, leaving the tumors exposed and more susceptible to immune attacks. So much so, the team found that when the mice were treated with Setanaxib, it increased the immune cell penetration of the tumors by as much as ten times, reducing tumor size by more than 50 percent. When combined with various immunotherapies, the treatment reduced tumor size by as much as 75 percent and approximately doubled the survival times.
"Immunotherapy for cancer has been a very exciting development, but still doesn't work in most patients,” says study author Professor Gareth Thomas. “Our results suggest that in many cases, treatment resistance is caused by CAF, and we think this can be overcome by targeting NOX4. GKT137831 hasn't yet been tested on cancer patients, but we hope may give immunotherapy drugs a much better chance of fighting cancer cells effectively; this technique could hugely improve the success rate of cancer immunotherapy."
The team says the next steps are to see if these results can be replicated in humans. The University of Southampton team has also received funding from Cancer Research UK to begin investigating how it might improve immunotherapy treatments for breast cancer patients.
The research was published in the journal Cancer Research.
Source: University of Southampton