They are often said to be "exhausted": the immune cells
(T cells) in a tumour which are not doing what they should: killing
tumour cells. However, these dysfunctional immune cells form a
highly active and dynamic group within the tumour, discovered
researchers from the Netherlands Cancer Institute and the
Israeli Weizmann Institute of Science. They published an article
on their study in scientific magazine Cell on Thursday 27
These "dysfunctional" cells have the capacity to multiply, and
their presence in the tumour helps the immune system better
recognise the tumour. That recognition is an essential prerequisite
for a good response to immunotherapy.
Future research will be aimed at finding out how immune therapy can
be used to increase the amount of these active cells in the
Researchers Anne van der Leun (Ton Schumacher lab in the
Netherlands Cancer Institute), Hanjie Li, Ido Yofe and Yaniv
Lubling (Weizmann Instituut) and coworkers worked cell by cell to
map out the gene activity of the immune infiltrate in tumour tissue
from 25 melanoma patients. Using the single cell
RNA-sequencing method, they were able to characterise and classify
nearly 47,000 immune cells, including nearly 30,000 T cells.
T cells in the tumour
T cells play an important role in immunotherapy against cancer,
particularly the killer T cells which have entered the tumour
environment from the blood. They have two jobs: identify the tumour
cells and destroy them. The defence mechanisms in tumour cells
cause them to lose the latter quality quite quickly, however.
The most important form of immunotherapy, the "checkpoint
inhibitors", which won the Nobel Prize in Physiology or Medicine in
2018, aims to re-enable these T cells to destroy the tumour cells
again. The big question now is why some patients respond really
well to immunotherapy while many others do not.
To find out, researchers are looking for the molecular
mechanisms underlying a successful response to immunotherapy. They
hope that, in the future, their findings will help doctors more
accurately predict which patients stand to benefit from
immunotherapy and aid the development of improved forms of
Looking at gene activity
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 tumour. 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 tumour cells. Instead, we
study the gene activity, so whether genes are switched on or
Not "dressed to kill"
Van der Leun and her coworkers discovered a large, active
population of "dysfunctional" T cells in tumour tissue from 25
melanoma patients which 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 tumour
was recognised," says Van der Leun. The newest dysfunctional T
cells, in particular, also proved capable of reproducing and
growing to a sizeable population within the tumour in a matter of
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
In addition to the large group of generally dysfunctional T
cells, the researchers also discovered a much smaller population of
T cells in the tumour tissue which were still "set to kill", but
which were apparently not specifically targeting tumour cells, as
their presence did not lead to improved recognition of the tumour.
"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
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.