What keeps tumor infiltrating T cells from being effector cells? (LSBR 1373) FELLOWSHIP
Project leader: Dr. Monika Wolkers (Dept. Hematopoiese, Sanquin Research)
PhD student: Benoit P. Nicolet (July 2014 – July 2018)
Research technician: Aurelie L.E. Guislain (Jan. 2014 – Aug. 2017)
CD8+ T cells are potent effector cells that recognize and kill infected cells and tumor cells. They do so by producing copious amounts of effector molecules, such as cytokines. In the past years, T cells have been used as a therapy for cancer. This resulted in remarkable effects, with patients being cured from the disease.
However, not every patient responds equally well to therapies with T cells. One of the problems is that T cells gradually lose their effector function within the tumors, allowing the tumor to grow.
We have therefore studied which mechanisms are involved in maintaining effective T cell responses against tumors.
We found that T cells in the tumor still make the RNA for specific cytokines, but fail to produce the protein that is required to clear the tumor cells. We identified a specific sequence in the RNA that is involved in this process.
In addition, we made technical advances to study RNA in T cells. This yielded several interesting insights in T cell biology. For instance, we found that the signals received by T cells from the environment all drive the protein production in a different fashion. This information will help us to arm T cells against the gradual exhaustion they experience within the tumor.
Furthermore, we found that human blood derived CD8 T cells are not uniform. We identified specific surface markers that can distinguish the bona fide killer CD8 T cells from another CD8 T cell population that bears features of T helper cells. Because our findings now allow us to identify the bona fide killer T cells, this should help to generate better T cell products for therapeutic approaches.