Amping up the immune system's T cells to improve their cancer-killing prowess
Combining immuno-oncology treatments like checkpoint inhibitors with other cancer-killing drugs is considered to be a key strategy for improving the response rate to immunotherapy. Now, a team of Canadian researchers is suggesting a new combination strategy for improving the response of the immune system’s T cells to immuno-oncology drugs, and it involves epigenetics.
A team led by the Princess Margaret Cancer Centre in Toronto discovered that chemotherapy drugs known as DNA hypomethylating agents directly affected the anti-tumor response of a specific type of T cell in samples from patients with several tumor types. Two genes were activated to improve the ability of the T cells to kill cancer cells, they reported in the journal Molecular Cell.
DNA hypomethylating agents are epigenetic drugs that work by removing specific chemical “tags” on DNA, thereby turning specific genes on and off and changing the function of cells.
The researchers had previously discovered that when mouse tumors were treated with epigenetic drugs, there was a surge in T cells infiltrating the cancer. If they removed the T cells, the therapy stopped working.
They decided to investigate the phenomenon further using samples from healthy people and from patients with melanoma, as well as breast, ovarian or colon cancer. Again they found that DNA hypomethylating agents enhanced the ability of T cells to kill cancer.
The team used next-generation single-cell mass cytometry technology to observe exactly what was happening to the T cells when the epigenetic therapy was applied. They found that after the drugs activated the two genes, there was an increase in granzyme and perforin proteins, which improved the ability of T cells to enter cancer cells and kill them.
Gaining a better understanding of the epigenetic forces in cancer to boost treatment strategies is a priority in oncology research. Boundless Bio spun off from the University of California, San Diego in 2019 to discover treatments targeting the epigenetic forces exerted by extrachromosomal DNA (ecDNA), ring-shaped DNA containing oncogenes that are highly expressed in aggressive cancers.
In 2018, a team at Mount Sinai School of Medicine in New York used CRISPR gene editing to discover an epigenetic process that drives drug resistance in melanoma. They found they could inhibit the process by combining a BRAF inhibitor with an investigational drug from Astellas called linsitinib.
The Canadian researchers believe their study of DNA hypomethylating agents could set the stage for future clinical trials of novel combination strategies in several tumor types. "Our goal for the future is to use this strategy combined with other immunotherapies to enhance anti-tumor immunity," said co-author Daniel De Carvalho, Ph.D., associate professor of medical biophysics at the University of Toronto, in a statement.