New research at the University of Alberta has revealed a way to increase the sensitivity to immunotherapy of a rare type of cells within a tumour that are responsible for treatment resistance and breast cancer progression. The study, recently published in the journal Cancer Letters, could pave the way to better treatment outcomes for patients.
The researchers looked at how to use a type of cell called gamma delta T-cells more effectively in immunotherapy to target breast cancer stem-like cells. T-cell immunotherapy is a promising new field, with researchers around the world working to develop treatments that use a patient’s own immune system to fight diseases such as cancer. However, most immunotherapy of this type focuses on the more conventional alpha-beta T-cells.
Image credit: U.S. Air Force photo by Senior Airman Tiffany Trojca via holloman.af.mil, Public Domain
According to Gabrielle Siegers, a research scientist with the Department of Oncology in the Faculty of Medicine & Dentistry, one advantage of gamma delta T-cells over the more commonly used alpha beta T cells is that they don’t cause graft versus host disease, a condition in which donated cells attack a person’s body. Gamma delta T-cells are also quicker to respond to stress signals in the body.
Together with her former student, Indrani Dutta, Siegers found that gamma delta T-cell immunotherapy very effectively eradicates breast cancer cells, but things become trickier with the stem-like cells, which are more resistant to targeting. However, it is these stem-like cells that most urgently need to be eliminated because of their power to cause cancer to recur.
“One of the reasons stem-like cells are quite resistant to chemotherapy is that they’re inactive—they’re not doing anything; they’re just sitting there. A lot of chemotherapy basically attacks the cell cycle, so if the cells aren’t actively dividing, the chemotherapeutic agents don’t tend to kill them,” said Siegers, who is also a member of the Cancer Research Institute of Northern Alberta. “The stem-like cells sit quiet until they get their chance. A lot of therapies will kill the bulk of the tumour and a patient will think they’re done and the cancer is all gone, but it just takes a few of these stem-like cells to regrow the whole tumour.”
Dutta and Siegers pursued several strategies to overcome the resistance of these breast cancer stem-like cells, and one in particular proved effective. They found that the stem-like cells shed higher levels of a protein called MIC class 1 chain-related protein A (MICA), which is an integral part of the cell-killing process because it's the recognition molecule that the gamma delta T-cells are looking for in their target.
“One way that tumour cells will try to evade targeting by the immune system is to cleave off those identifiers from their exterior. Basically, the tumour cells send out proteases that are like little scissors: they come along and snip off the recognition molecules so the cells can hide from the immune system,” said Siegers.
For the gamma delta T-cells to recognize the more resistant stem-like cells, these recognition molecules need to stay intact—which can be accomplished by inhibiting those “scissor” proteases, called ADAMs. While other methods these resistant cells use to evade gamma delta T-cells need to be explored, Siegers said managing the shedding of MICA is an important step forward.
“The ability for gamma delta T-cells to kill this dangerous subset of breast cancer cells would make a huge difference for treatment of breast cancer patients.”
Source: University of Alberta