A newly discovered receptor in T-cells — immune cells with the ability to kill tumors — makes these cells able to recognize and eliminate several cancer types, without harming healthy cells, through an unconventional immunological mechanism that isn’t fully understood yet, a new study shows.
This finding may pave the way for cell-based immunotherapies that are more universal than those currently in existence.
The study, “Genome-wide CRISPR–Cas9 screening reveals ubiquitous T cell cancer targeting via the monomorphic MHC class I-related protein MR1,” was published in Nature Immunology.
To be able to kill cancer cells, T-cells use a receptor protein called a T cell receptor (TCR), which essentially “looks” at the proteins being produced by a cell. If those proteins are abnormal — for example, if the cell is cancerous or infected with a virus — the T-cell can become activated to kill the abnormal cell.
Improving the efficacy of this process is a goal of many cancer immunotherapies. For example, T-cell receptor therapies use natural mechanisms of T-cells to fight cancer, equipping T-cells with a new TCR that guides them to attack cells with a particular cancer protein.
There are some problems with this approach, however. One is that cancers are different, and targeting a single protein makes a therapy specific for only one or a few cancer types. The other problem is the reliance on a group of molecules called major histocompatability complex (MHC), whose sequence varies greatly from person to person.
The MHC complex is required in the process of T-cell activation. In fact, cells known as antigen-presenting cells, which essentially tell T-cells what their targets are, do so by “presenting” at their surface, pieces of the target protein bound to the MHC complex. But since MHCs are not equal for all people, therapies relying on this mechanism only work for a certain group of patients.
In the new study, researchers identified a kind of T-cell with a novel TCR that doesn’t act through MHC, but through a different protein called MR1 (major histocompatibility complex class I-related gene protein).
MR1 is known to play a role in how some kinds of T-cells recognize certain bacterial metabolites, but it has not been implicated in cancer immunity. Importantly, unlike MHC, the sequence of MR1 doesn’t vary much between individuals.
The researchers tested T-cells expressing this new receptor — dubbed MC.7.G5 cells — against different types of cancer cell lines (including lung, melanoma, leukemia, breast, prostate, and ovarian) in dishes.
MC.7.G5 cells were able to kill all of these cell types with greater than 80% efficiency, and near 100% efficiency for most. Blocking MR1, but not MHC, diminished this effect, confirming that it was being mediated by MR1.
However, MC.7.G5 cells showed virtually no killing effects against a variety of non-cancerous cell lines from these same organ types. This suggests that these cells were able to specifically recognize and kill cancer cells, but not healthy cells — though it should be noted that “healthy” cells in dishes are considerably different biologically than those in a living body, so more research will be needed.
Then, the researchers injected MC.7.G5 cells into mice with leukemia that had been engineered to have human-like immune systems. After 18 days, less than 10% of the cells in the bone marrow of MC.7.G5-treated mice were leukemia cells. By comparison, this value was well over 75% for untreated mice. Similarly, MC.7.G5-treated mice survived significantly longer (about 60 vs. 30 days post-injection).
Finally, the researchers took T-cells from an individual with melanoma, and modified these cells to express the same MR1-specific TCR as MC.7.G5 cells. In dishes, these T-cells were able to kill melanoma cells from the original patient and from other people, suggesting some universality to the effect.
“Cancer-targeting via MR1-restricted T-cells is an exciting new frontier,” study co-author Andrew Sewell, PhD, a professor at Cardiff University, said in a press release. “It raises the prospect of a ‘one-size-fits-all’ cancer treatment; a single type of T-cell that could be capable of destroying many different types of cancers across the population.”
More research will be necessary before this finding is translated into use in people.
“So far, the power of these immune cells to kill cancer cells has been tested in a lab dish and in mice. At the moment, this is very basic research and not close to actual medicines for patients,” Daniel Davis, PhD, a professor at Manchester University and who was not affiliated with the study, wrote in an expert opinion.
“There is no question that is a very exciting discovery, both for advancing our basic knowledge about the immune system and for the possibility of future new medicines,” he said.
