Immunotherapy has been very successful in some cancer patients, but not in others. This emerging treatment option stimulates the patients' own immune cells to fight cancer cells. One of the possible strategies to improve the treatment outcome is to stimulate immune cells not just from the outside - as current immunotherapies do - but from within their nucleus as well. Fred van Leeuwen and Heinz Jacobs and their research groups at the Netherlands Cancer Institute join forces to investigate this. They have received a TOP grant of 675.000 Euro (5 years) from ZonMw, the Netherlands Organization for Health Research and Development.
One needs to dive deep into the human cell to understand why Van Leeuwen and Jacobs explore this topic. A journey into the core of the cell: the nucleus, containing DNA. Cells wrap their DNA around proteins to form a compact package that fits into their nucleus. Another type of protein can make small, so-called epigenetic changes to the DNA package to activate or silence part of the genetic code, changing the behavior of the cell.
Immune cells called T-cells change their behavior multiple times during their lifespan. "They wait until they bump into something foreign like a bacteria or a tumor, upon which they become active, multiply and attack", Van Leeuwen explains. "We have discovered that immune cells lacking a protein called DOT1L look like they've already been activated without having bumped into something foreign. Apparently, this DOT1L epigenetic factor causes T-cells to change their appearance."
Their TOP grant allows Van Leeuwen and Jacobs to determine whether these seemingly activated immune cells can actually help in combatting cancer. They'll try to unravel how the absence of DOT1L causes immune cells to change their appearance, and how these cells actually behave. Do they act according to their looks? Can they fight cancer cells?
"Interestingly, a drug that inhibits DOT1L is already being tested in a phase 1 clinical trial for patients with a specific form of leukemia", says Van Leeuwen. "These patients have a gene defect that causes DOT1L to be hyperactive. Once we understand how the DOT1L protein influences the behavior of immune cells, this inhibitor could possibly be used to push them towards fighting cancer cells."
ZonMw TOP grants offer strong research groups the opportunity to engage in new, risky lines of research. The grants are intended to give them the opportunity to innovate in their research lines, in terms both of content and of collaboration. More information about TOP grants.