Making T cells more effective against cancer: €1 million KWF grant for Monika Wolkers

Tumor-infiltrating lymphocytes (TILs) are a specific type of T cell that can kill cancer cells, both naturally inside the body and, increasingly, when administered as a cellular therapy. Unfortunately, these cells quickly lose their potency. Wolkers' mission is to discover how to ensure these killer cells last longer and remain better equipped to fight tumors.

How tumors inhibit T cells

A TIL's primary weapons are proteins. Either proteins that directly destroy tumor cells, or those that recruit other immune cells to finish the job. Unfortunately, when T cells get in the vicinity of a tumor, the tumor does everything it can to neutralize them. It does this by secreting signaling proteins, as well as making direct contact with the T cell to flip an "off switch."

Wolkers wants to determine exactly what happens to T cells during this process. Which proteins are produced in lower, or perhaps higher quantities in an exhausted T cell? The answer could hold the key to novel therapies.

Measuring protein levels

Measuring proteins inside a cell is no simple task. For years, scientists relied on the amount of mRNA in a T cell as a proxy to predict protein production, simply because measuring RNA is much easier. However, Wolkers' research has long shown that RNA levels do not translate one-to-one into protein levels. Recently, Wolkers examined over 300 proteins in active and exhausted T cells from lung cancer patients. The result? Only a third of the proteins had corresponding RNA levels. In short, measuring actual protein concentrations is essential to pinpointing where exhausted T cells differ.

Differences between active and exhausted T cells

With this KWF grant, Monika and her colleagues will map out the differences between active and exhausted T cells. She will study these variations at the protein level and compare them directly to RNA levels. With colleagues Kaspar Bresser and Arjan Hoogendijk, Wolkers previously developed a technology that allows more than 6,000 proteins across 30,000 T cells to be identified and quantified.

New leads for cancer therapies

By gaining a deeper understanding of which proteins make the difference and how cells regulate production to fight tumor cells, researchers can unlock new avenues for treatment, both within a patient's body and in the lab, when culturing T cells harvested from tumor tissues.