The creation of “super-soldiers” of specific white blood cells to stimulate an anti-tumor response has been revealed in a series of elegant experiments by Princess Margaret’s researchers.
Research led by Ph.D. candidate Helen Loo Yau, postdoctoral fellow Dr. Dr. Emma Bell and Chief Scientist Daniel D. De Carvalho describes DNA transforming epigenetic therapy that can turn deadly immune T cells into “super-soldiers” by increasing their ability to kill cancer cells. .
Their findings could improve immunotherapy, a new paradigm in cancer treatment that is currently effective for a minority of cancer patients. Some patients respond well to immunotherapy, with their tumors rapidly degenerating, but others respond only partially or not at all. Clinicians and scientists around the world are working to understand why immunotherapy only helps some patients.
The research is published in Cell molecular, February 19, 2021.
Our goal for the future is to use this strategy in combination with other immunotherapies to strengthen tumor immunity. We are considering a future clinical trial where we will collect T-cells from the patient for treatment with epigenetic therapy in the laboratory. This could effectively expand the army of cancer-killing cells creating an ‘army of super soldiers’. These cells can then be re-introduced into the patient, to strengthen their immune response to the tumor. “
Dr. De Carvalho, Associate Professor, Department of Medical Biophysics, University of Toronto
Dr. De Carvalho’s laboratory first saw an increase in T-cell infiltration in mouse tumors treated with epigenetic therapy. Once the T cells were removed, the treatment stopped working, suggesting that the T cells were contributing to the success of the treatment.
Deceived by this finding, the researchers decided to apply this epigenetic DNA modification therapy directly to T cells in the laboratory. They removed T cells from healthy human donors, as well as patients with melanoma, breast, ovarian and colorectal cancers. Their results confirmed that epigenetic therapy enhanced the ability of T-cell cancer killers.
Epigenetics works by adding or removing chemical ‘tags’ to DNA. Just like accessible post-it notes, these tags help specify which genes can be turned on or off. Simply put, you can alter cell function by using drugs that alter these epigenetic tags.
In fact, the researchers found that an available chemotherapy drug removed specific epigenetic tags that suppressed genes in a subset of key genes in T cells. Removing the These tags turned these genes back on, and activated the “turbocharge” of the T cells to make them more efficient killing machines.
The researchers found two specific genes that were activated by epigenetic therapy and that were responsible for the T cells being better at killing the cancer cells.
Large unilateral, single-cell cytometry analyzes – the next-generation technology, which accounts for single-cell and drug response – revealed an increase in the numbers of granzyme and perforin proteins, which T cells secrete. used to accomplish the act of killing. When released, as a lethal swat team, perforins will be able to drill holes in a cell ball to allow granzymes to enter an infectious or cancerous cell to complete the work of killing it.
“T-cells have become a kind of ‘excellent soldiers’, with well-activated molecules – with bigger and better weapons – to destroy the cancer cells,” explained Dr De Carvalho, adding. to the paper a detailed description of the molecular approach of the process. happens.
A key novelty in the paper is the use of epigenetic therapy to influence the behavior of genes in the T-cell. Most research on epigenetic therapies focuses on their effect on cancer cells. However, this paper looks at how our immune cells respond, giving us an insight into how we can stimulate the anti-tumor activity of our immune systems.
The emerging field of epigenetic therapy seeks to influence genetic activity without altering DNA sequence – making this an interesting therapeutic pathway of cancer study.
“Genetic manipulation of immune cells for treatment is not very difficult. It is even more complex and expensive in clinical implementation,” says Dr. De Carvalho, “Our work sets the platform for studies. clinical combination of epigenetics with other immunotherapy strategies. “
Source:
University Health Network
Magazine Reference:
Yau, HL, et al. (2021) DNA hypomethylating agents increase the activity and cytolytic activity of CD8+ Cells T. Cell molecular. doi.org/10.1016/j.molcel.2021.01.038.