Turbocharging the killing power of immune cells against cancer

February 19, 2021

Creating "super soldiers" of specific white blood cells to boost an anti-tumour response has been shown in a series of elegant experiments by Princess Margaret researchers.

Research led by Ph.D. candidate Helen Loo Yau, Post-doctoral fellow Dr. Emma Bell and Senior Scientist Dr. Daniel D. De Carvalho describes a DNA modifying epigenetic therapy that can transform immune killer T-cells into "super soldiers" by boosting their ability to kill cancer cells.

Their findings could potentially enhance immunotherapy, a new paradigm in cancer treatment currently effective for a minority of cancer patients. Some patients respond well to immunotherapy, with their tumours drastically shrinking in size, 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 Molecular Cell, Feb 19, 2021.

"Our goal for the future is to use this strategy combined with other immunotherapies to enhance anti-tumor immunity," says Dr. De Carvalho, Associate Professor, Department of Medical Biophysics, University of Toronto. "We imagine a future clinical trial where we collect T-cells from the patient for treatment with epigenetic therapy in the lab. This could expand the army of cancer killing cells effectively creating an 'army of super soldiers'. These cells can then be re-infused into the patient, to potentially enhance their built-in immune response to the tumour."

Dr. De Carvalho's lab first observed an increase in T-cell infiltration in mouse tumours treated with epigenetic therapy. When they removed the T-cells, the therapy stopped working, suggesting that the T-cells were contributing to the treatment success.

Intrigued by this finding, the researchers 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 from patients with melanoma, breast, ovarian and colorectal cancer. Their results proved that the epigenetic therapy enhanced the T-cells cancer killing ability.

Epigenetics works through addition or removal of chemical 'tags' to DNA. Much like detachable post-it notes, these tags help to specify which genes can be turned on or off. Simply, you can change the function of a cell using drugs that change these epigenetic tags.

In essence, the researchers found that an available chemotherapy drug removed specific epigenetic tags that were keeping genes off in a subset of key genes in T-cells. Removing these tags turned these genes back on, and acted to "turbocharge" the T-cells to become more effective killing machines.

The researchers discovered two specific genes that were activated by the epigenetic therapy and which were responsible for the T-cells to become better at killing the cancer cells.

High-dimensional, single-cell mass cytometry analyses - a next generation technology, which profiles single cells and drug response - revealed an increase in the numbers of granzyme and perforin proteins, which T-cells use to carry out their killing function. When unleashed, like a lethal swat team, perforins are able to punch holes in a cell's membrane to allow granzymes to enter into an infected or cancerous cell to finish the job of killing it.

"The T-cells became sort of 'super soldiers', with highly activated molecules - with bigger and better weapons - to destroy the cancer cells," explains Dr. De Carvalho, adding the paper describes in detail the molecular mechanism of how the process occurs.

A key novelty in the paper is using epigenetic therapy to influence the behaviour 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 insight into how we can boost the anti-tumour activity of our immune systems.

The emerging field of epigenetic therapy seeks to influence genetic activity without actually modifying the sequence of DNA - making this an exciting therapeutic avenue of cancer research.

"Genetic manipulation of immune cells for treatment is not trivial experimentally. It's even more complicated and expensive in clinical implementation," says Dr. De Carvalho, "Our work sets the stage for clinical investigations combining epigenetics with other immunotherapy strategies."
-end-
This research was supported by Canadian Institutes of Health Research (CIHR), Princess Margaret Cancer Foundation, Terry Fox Research Institute, Ontario Institute for Cancer Research, Canadian Cancer Society Innovation Award, and the Scotiabank Research Chair.

Competing Interests

Dr. Daniel De Carvalho received research funds from Pfizer and Nektar therapeutics. Dr. De Carvalho is co-founder and shareholder of DNAMx, Inc. Christian Klein is employed, owns stocks, patents and royalties at Roche. John Stagg is a permanent Scientific Advisory Board member and owns stocks of Surface Oncology.

About Princess Margaret Cancer Centre

Princess Margaret Cancer Centre has achieved an international reputation as a global leader in the fight against cancer and delivering personalized cancer medicine. The Princess Margaret, one of the top five international cancer research centres, is a member of the University Health Network, which also includes Toronto General Hospital, Toronto Western Hospital, Toronto Rehabilitation Institute and the Michener Institute for Education at UHN. All are research hospitals affiliated with the University of Toronto. For more information: http://www.theprincessmargaret.ca

For media inquiries, please contact:

Alexandra Radkewycz
Senior Public Affairs Advisor
Princess Margaret Cancer Centre, University Health Network
Phone: 416 946 2846
Email: Alexandra.Radkewycz@uhn.ca

University Health Network

Related Science Articles from Brightsurf:

75 science societies urge the education department to base Title IX sexual harassment regulations on evidence and science
The American Educational Research Association (AERA) and the American Association for the Advancement of Science (AAAS) today led 75 scientific societies in submitting comments on the US Department of Education's proposed changes to Title IX regulations.

Science/Science Careers' survey ranks top biotech, biopharma, and pharma employers
The Science and Science Careers' 2018 annual Top Employers Survey polled employees in the biotechnology, biopharmaceutical, pharmaceutical, and related industries to determine the 20 best employers in these industries as well as their driving characteristics.

Science in the palm of your hand: How citizen science transforms passive learners
Citizen science projects can engage even children who previously were not interested in science.

Applied science may yield more translational research publications than basic science
While translational research can happen at any stage of the research process, a recent investigation of behavioral and social science research awards granted by the NIH between 2008 and 2014 revealed that applied science yielded a higher volume of translational research publications than basic science, according to a study published May 9, 2018 in the open-access journal PLOS ONE by Xueying Han from the Science and Technology Policy Institute, USA, and colleagues.

Prominent academics, including Salk's Thomas Albright, call for more science in forensic science
Six scientists who recently served on the National Commission on Forensic Science are calling on the scientific community at large to advocate for increased research and financial support of forensic science as well as the introduction of empirical testing requirements to ensure the validity of outcomes.

World Science Forum 2017 Jordan issues Science for Peace Declaration
On behalf of the coordinating organizations responsible for delivering the World Science Forum Jordan, the concluding Science for Peace Declaration issued at the Dead Sea represents a global call for action to science and society to build a future that promises greater equality, security and opportunity for all, and in which science plays an increasingly prominent role as an enabler of fair and sustainable development.

PETA science group promotes animal-free science at society of toxicology conference
The PETA International Science Consortium Ltd. is presenting two posters on animal-free methods for testing inhalation toxicity at the 56th annual Society of Toxicology (SOT) meeting March 12 to 16, 2017, in Baltimore, Maryland.

Citizen Science in the Digital Age: Rhetoric, Science and Public Engagement
James Wynn's timely investigation highlights scientific studies grounded in publicly gathered data and probes the rhetoric these studies employ.

Science/Science Careers' survey ranks top biotech, pharma, and biopharma employers
The Science and Science Careers' 2016 annual Top Employers Survey polled employees in the biotechnology, biopharmaceutical, pharmaceutical, and related industries to determine the 20 best employers in these industries as well as their driving characteristics.

Three natural science professors win TJ Park Science Fellowship
Professor Jung-Min Kee (Department of Chemistry, UNIST), Professor Kyudong Choi (Department of Mathematical Sciences, UNIST), and Professor Kwanpyo Kim (Department of Physics, UNIST) are the recipients of the Cheong-Am (TJ Park) Science Fellowship of the year 2016.

Read More: Science News and Science Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.