A University of Alberta research team has identified a DNA structure that activates the immune system in cancer cells that are usually resistant to immunotherapy, offering hope of new, more effective treatments for colorectal and other cancers.
Eighty per cent of colorectal cancers are resistant to currently available immunotherapies, explains principal investigator Kristi Baker, associate professor in the departments of oncology and medical microbiology and immunology.
That's because they fail to activate a protein known as STING (stimulator of interferon genes) that is key to antitumour immune responses within cancer cells. In recently published research, Baker's team identifies and sequences a DNA molecule shown to activate STING resistant colorectal cancer cells.
"What we're thinking is that by combining immunotherapies with these DNA structures that can super-activate STING, maybe we can induce a much stronger immune response in the patients who normally don't respond," says Baker.
Sixty-nine Canadians are diagnosed with colorectal cancer each day, according to Colorectal Cancer Canada, and the Canadian Cancer Society says it is the second leading cause of cancer death in men and the third for women.
The team carried out its experiments in cell cultures, animal models and human "organoids," which are 3D models made from donated human tumour samples. DNA sequencing revealed the highly repetitive DNA structures that trigger STING. The team is now using atomic force microscopy to identify other structures that might also be beneficial.
"When we added the highly repetitive DNA to that really poorly immunogenic tumour type, we could see better STING activation and induce cytotoxic T cells that actually kill tumour cells," says first author Shayla Mosley, a PhD candidate in oncology who led the work as part of her thesis.
"That tells us that this is a way we can improve the immune response against these poorly immunogenic cancers," says Mosley. "We'd like to combine that with immunotherapies and really see an improved response and a decrease in the growth of those tumours."
Mosley notes that radiation and some chemotherapy treatments also increase the presence of the STING-activating DNA structures. By combining treatments, the aim is to create enough of the structures to activate STING and prompt a sufficient immune response to kill the tumours.
"Tumours start to adapt whenever you hit them with a therapy, so if you have another therapy ready that you can then give to your patient, you stay one step ahead in treating the cancer and preventing it from growing," Baker says. "The better we understand what it is about these DNA structures that activates STING, the better we will be able to make a therapy based on this."
Baker gives credit to patients who have donated their expertise and their tissues to support her research through Applied Research & Patient Experience.
Mosley, who hopes to defend her thesis this summer, notes that STING has been implicated in other diseases beyond cancer, including viruses, rheumatoid arthritis and Alzheimer's.
"We're learning in our work how to make a structure that will turn the STING pathway on," she says. "Perhaps in the future we can flip that and make a structure that will turn it off in these autoimmune diseases."
Shayla Mosley won numerous student awards to support her PhD studies, including the Dr. Herbert Meltzer Memorial Fellowship, the University of Alberta Doctoral Recruitment Scholarship and the Yau Family Foundation Studentship.
Kristi Baker is a member of the Cancer Research Institute of Northern Alberta and the Women and Children's Health Research Institute. Some of this research was carried out at the U of A's Advanced Cell Exploration Core and Cell Imaging Facility.
