April 1, 2019Oncology
Immunotherapy has led to remarkable results for some patients' cancers, eradicating difficult-to-treat tumors and, in some cases, causing complete remission of disease. But many patients' tumors do not respond to immunotherapy treatments. In addition, some immunotherapy treatments, such as CAR T cells and immune checkpoint inhibitors, are limited by the life span of T cells. Cancer-fighting T cells inside the tumor can get exhausted and die. Therefore, studies are underway to explore ways to help T cells used for immunotherapy not only last longer but replicate and grow.
According to an article published in Science (29 March 2019), dying cancer cells release potassium, which can reach high levels in some tumors. In addition, the authors observed that potassium appears to cause T cells to maintain a stem-cell-like quality, or stemness, that is closely tied to their ability to eliminate cancer during immunotherapy. The findings suggest that increasing T cells' exposure to potassium -- or mimicking the effects of high potassium -- could make cancer immunotherapies more effective.
The authors previously established that high levels of potassium inside tumors released by dying cancer cells can shut off cancer-killing T cells that have invaded the tumor. In the new study, the authors showed that growing T cells under conditions of high potassium also preserves the stemness of the T cells. This means that, in the tumor, the stem-cell-like T cells have the ability to replicate themselves, but they aren't able to mature into killer immune cells. By keeping T cells in this state, the tumors can avoid attack and continue to grow. This could explain how a cancer could grow despite the presence of T cells that would seemingly be able to fight the cancer.
However, when the stem-cell-like T cells are removed from the tumor, grown to large numbers in the lab, and then returned to the patient - as they are in a primary immunotherapy strategy called adoptive cell transfer -- the stem-cell-like T cells can mature into killer cells that can attack the tumor. The preserved stemness of T cells -- that is, their ability to self-renew indefinitely and respond to stimulation to become cancer-fighting cells -- may be what allows adoptive cell transfer therapy to be successful.
The study also explored preserving T cells' stemness with high potassium levels for therapeutic use. Results showed that T cells grown in the presence of extra potassium and then transplanted into mice, shrank primary and metastatic melanoma tumors better than T cells grown in normal levels of potassium. The study also found that, when exposed to a high concentration of potassium, both T cells isolated from patient tumors as well as genetically engineered anticancer T cells had higher levels of markers associated with continued growth and improved immunotherapy outcomes. Finally, the study demonstrated that when they used specific drugs to mimic potassium's effects on T cells in mice, this improved the T cells' ability to continue to grow and eliminate tumors. According to the authors, this means that such a drug could potentially be used to induce stemness in T cells as a strategy to enhance cancer immunotherapies.