Cancer immunotherapies are becoming increasingly promising as a standard-of-care treatment. However, despite their promise, they still don't work for everyone. Now, researchers may have both found why this is- and a way to resolve the issue.
Checkpoint inhibitors are a type of immunotherapy that work by targeting specific proteins, such as PD-L1, that exist on tumor cells and signal the body's immune system not to attack them. Although effective in some cases, patients can develop resistance to these therapies if their cancer has spread beyond its initial location to form additional tumors on their liver.
For their study, the researchers simulated this process by implanting mice with cancer cells under the skin and then either in their liver or lungs. In doing so, they found that, unlike in the lungs, cancer cells in the liver were 'uniquely suppressive'. There, it appeared they were able to take advantage of the liver's signaling mechanisms to retrain the immune system to ignore cancer cells both there and elsewhere in the body.
As such, the researchers found that after anti-PD-1 treatment, mice with secondary cancers in their livers had significantly lower survival rates than those with cancer in their lungs.
To find out why this was the case, the researchers later conducted single-cell analyses and found that liver tumors were able to change which genes were expressed in regulatory T cells (immune cells that suppress the immune response also known as 'Tregs') and from there, multiple other immune system cells too. Rather than a difference in the quantity of T cells, the researchers found that cancer in the liver led to a difference in their quality.
As such, the researchers tested two drugs to see if they could override this effect. While both were effective in restoring the efficacy of anti-PD-1 therapy, they found that the second drug, an anti-CLTA-4 compound that targets regulatory T cells directly and depletes their numbers, was more effective.
"We've never had this kind of precision in immunotherapy in the past," says James Lee, lead author of the research. "What if, right from the start, you could use a drug that depletes Tregs as a complement to immunotherapy in patients with liver metastasis?"