Molecular Cell: DNA hypomethylating agents increase activation and cytolytic activity of CD8+ T cell

In a new study, researchers from the Princess Margaret Cancer Center of the Canadian University Medical Network and the University of Toronto improved anti-tumor responses by carrying out a series of elegant experiments to construct "super soldiers" with specific leukocytes. Specifically, they describe an epigenetic therapy that modifies DNA and can convert killer T cells into "super soldiers" by enhancing their ability to kill cancer cells. The results were published in Molecular Cell, entitled "DNA hypomethylating agents increase activation and cytolytic activity of CD8 + T cells". The corresponding author of the paper is Dr. Daniel D. De Carvalho of Princess Margaret Cancer Center. The first author of the paper is Helen Loo Yau, PhD student at Princess Margaret Cancer Center, and Dr. Emma Bell, postdoctoral researcher.

Their findings may enhance immunotherapy, a new model of cancer treatment that is currently effective for a small number of cancer patients. Some patients respond well to immunotherapy with dramatic reduction in tumor size, but others respond only partially or not at all. Clinicians and scientists around the world are trying to understand why immunotherapy is only helpful for some patients.

Dr. De Carvalho said, “Our future goal is to use the strategy to combine with other immunotherapies to enhance anti-tumor immunity. We imagine future clinical trials: we collect T cells from patients and perform epigenetic therapy in the laboratory. This may expand the army that kills cancer cells (i.e., cells that kill cancer cells) and effectively construct a 'super soldier army'. These cells can then be reinjected into the patient, thereby potentially enhancing their intrinsic immune response to the tumor.”

Dr. De Carvalho's laboratory first observed that T cell infiltration was increased in tumors from mice treated with epigenetic therapy. When they removed these T cells, this therapy no longer worked, suggesting that these T cells played a promoting role in the success of this therapy.

These researchers, interested in this finding, set out to apply this epigenetic DNA-modifying therapy directly to T cells in the laboratory. They isolated T cells from healthy human donors as well as patients with melanoma, breast, ovarian, and colorectal cancers. Their results demonstrate that this epigenetic therapy enhances the cancer-killing ability of these T cells.

Epigenetics works by adding or removing chemical "tags" to DNA. Like removable convenience stickers, these labels help specify which genes can be turned on or off. Simply put, you can use drugs that alter these epigenetic signatures to change the function of cells.

In essence, these researchers found that an available chemotherapeutic drug removes specific epigenetic signatures that give way to genes in a proportion of key genes of T cells in a closed state. Removing these tags allows these genes to be returned on and act as a “turbo”, making these T cells a more effective cancer-killing machine.

These researchers discovered two specific genes activated by this epigenetic therapy that are responsible for these T cells becoming better at killing cancer cells.

High-dimensional single-cell mass cytometry analysis—a new generation of technology that can dissect single-cell and drug responses—has found that T cells increase the number of granzyme and perforin proteins used to perform killing function. When granzymes and perforin are released, like a fatal special police force, perforin is able to punch holes in the cell membrane and allow granzymes to enter infected cells or cancer cells and complete the task of killing these cells.

Dr. De Carvalho explained, “These T cells become some kind of 'super soldier' and carry highly activated molecules, with better weapons, to destroy cancer cells.” The molecular mechanism of how this process occurs is described in detail.

A key innovation in the paper is the use of epigenetic therapy to affect the behavior of genes in T cells. Most studies on epigenetic therapies have focused on their effects on cancer cells. However, the paper focuses on how our immune cells respond, which provides new implications for how we improve the anti-tumor activity of the immune system.

This emerging field of epigenetic therapy aims to influence genetic activity without actually modifying the sequence of DNA, thus making it an exciting therapeutic avenue for cancer research.

Dr. De Carvalho said, “It is not experimentally simple to genetically manipulate immune cells for treatment. Its clinical application is more complex and expensive. Our study lays the foundation for clinical research that combines epigenetics with other immunotherapeutic strategies.”