Anne van der Leun: “Scientists all over the world have been working on identifying T cells for years now. Only in more recent years have we started looking at the interplay between various cells in the entire micro-environment of the tumor. Using single-cell sequencing, a technique developed in recent years, we can now do this at individual cell level. We do not look at the DNA blueprint itself, as is often done with tumor cells. Instead, we study the gene activity, so whether genes are switched on or off.”
Van der Leun and her coworkers discovered a large, active population of “dysfunctional” T cells in tumor tissue from 25 melanoma patients who were not “dressed to kill”. However, contrary to what has been assumed until recently, these cells were not at all exhausted. In other areas, they were teeming with activity. “The more dysfunctionality we saw, the better the tumor was recognized,” says Van der Leun. The newest dysfunctional T cells, in particular, also proved capable of reproducing and growing to a sizeable population within the tumor in a matter of days.
Schumacher: “So, we should not see these cells as markers of a completely exhausted T cell-based immune system, but rather as a sign that the immune system actively recognizes the patient's tumor cells.”
In addition to the large group of generally dysfunctional T cells, the researchers also discovered a much smaller population of T cells in the tumor tissue which were still “set to kill”, but which were apparently not specifically targeting tumor cells, as their presence did not lead to improved recognition of the tumor. “They may be important in another way, we just don't know how yet,” says Van der Leun. “For now, they may best be called 'bystander cells'”. Interestingly, the ratio of “bystanders” and “dysfunctional but active” cells varied strongly between patients.
Hanjie Li en Anne van der Leun, Ido Yofe, Yaniv Lubling et al., 'Dysfunctional CD8+ T cells form a proliferative, dynamically regulated compartment within human melanoma',
Cell 27 December 2018. DOI: 10.1016/j.cell.2018.11.043
The corresponding at the NKI is Ton Schumacher.
This study was funded by Merck KGaA, Darmstadt, Germany.