tumors consist of a mix of actively multiplying cells and areas of dead tissue. Previous research has found that tumors can repress the immune cells that act against them but until now, it wasn’t known how. New research, published online in Nature, found that cells within tumors release potassium into the extracellular space upon dying. Potassium is an ion that is usually found at high concentrations within cells and not outside them. The increased level of potassium in the extracellular tumor environment dulled the activity of T cells, a specialised effector cell of the immune system, preventing their anti-tumor function.
The researchers molecularly engineered tumor-specific T cells to increase their capacity to remove potassium from the cell. This created T cells which could effectively function to stimulate an anti-tumor immune response despite the elevated potassium environment surrounding them. The cells were engineered to express more molecular pumps specifically to deport excess potassium from the cell. Boosting the cells’ ‘potassium export’ capabilities prevented the high levels of intracellular potassium accumulation responsible for cellular dysfunction.
Modifying the T cells in this way enhanced the clearance of tumors and survival rates in mice with skin cancer.
Dr Rahul Roychoudhuri, group leader in the Lymphocyte Signalling and Development programme at the Babraham Institute and an author on the paper, said: “While ions such as calcium are known to play critical roles in the activation of T cells when they encounter foreign invaders and cancer cells, very little was known about how extracellular potassium might affect this. Surprisingly, we found that high levels of potassium, which was released by dying cells in tumors, had very little effect on calcium but blocked activation of a cellular signalling pathway called the PI3K pathway when T cells encountered tumor antigens. We have a lot of experience studying the PI3K pathway at the Institute so were well positioned to help understand the mechanisms by which potassium was blocking T cell activation.”
This research uncovers a new mechanism by which tumors act to block anti-tumor function and identifies new target points for the design of new immune-based therapies for cancer. Dr Nicholas Restifo, lead author from the National Cancer Institute, said: “The findings provide new insights into how ionic imbalances in the tumor microenvironment can powerfully impede the functions of immune cells infiltrating tumors. We’re particularly excited about how this may help us to develop new therapies to activate immune function in cancer patients.”