To be able to fight your enemy, you must first know who that
enemy is. The same applies to the immune system: to - for example -
be able to switch off tumor cells, the T cells of our immune system
must first recognize the tumor as a threat.
To their surprise, researchers from the Netherlands Cancer
Institute saw that in certain cancer types only a small part of the
army of T cells that have invaded a tumor is capable of doing so.
This could be a - until now unexposed - cause of the limited
clinical success of immunotherapy in those cancer types.
Monday, December 3, Wouter
Scheper, Sander Kelderman and others published an article in
Nature Medicine. Ton Schumacher
was the research leader (the Netherlands Cancer Institute and
Key players in the immune response against cancer cells are T
cells. They have a double function: they learn to recognize the
tumor cell and then destroy it. Immunotherapy against cancer, such
as treatment with checkpoint inhibitors, is mainly aimed at making
T cells better destroyers, for example when they are 'exhausted'
and cannot kill the tumor cell.
New technology to research recognition
But first of all, T cells must recognize cancer cells as tumor
cells, otherwise they will not take action. It has not been
possible to research the recognition capacity of T cells
independently of their destruction capacity in the tumor until
Researcher Wouter Scheper from Ton Schumacher's group at the
Netherlands Cancer Institute and his colleagues have now developed
a technology that allows them to examine which T cells in a tumor
are able to recognize a tumor cell and which are not: they build
the T cell receptors into healthy T cells and then test them on
tumor tissue from the same patient.
How does a T cell recognize a tumor cell?
Our immune system works very specifically. T cells recognize
tumor cells - as they do with viruses - via a protein on their cell
membrane: the T cell receptor. This very specifically recognizes a
protein (an antigen) on the tumor cell. Individual T cells differ
from each other in DNA sequence and thus in the antigen specificity
of their T cell receptor.
Which T cell recognizes the tumor cell?
To test the tumor specificity of T cells, the researchers
identified the DNA sequence of T cell receptors of a large number
of T cells from tumors of individual patients with ovarian cancer
and colorectal cancer. Then, with genetic manipulation, they
transferred the characteristic needed to make those receptors into
healthy and fit T cells from the blood of random, healthy
'That way we knew for certain that the T cells that we were going
to research were not yet exhausted,' says Scheper. 'We then tested
on pieces of tumor tissue whether these fit T cells, genetically
adapted with T-cell receptors from the tumor, can recognize the
tumor cells of the same patient.' This was not the case with a
large proportion - 5 to 10% - of the T cells.
New and troublesome
It was not an easy job. Scheper: 'The problem was mainly in the
large number, about 100, of unique T cell receptors that we tested.
The transfer of T cell receptors to healthy T cells and the
functional testing of T cell receptors against unmanipulated tumor
material has not been done on this scale in the field before.'
Why do so few T cells recognize the
Wouter Scheper: 'We think there are two main reasons. The first
is that the majority of the T cells that you find in tumors very
specifically recognize antigens that have nothing to do with the
tumor. We also have data to support this, because we saw a number
of T cell receptors that have learned to recognize antigens from
viruses earlier in their lives. We think that these types of T
cells are drawn to the tumor by an inflammatory response in that
tumor. But it is also possible that many of the T cells in tumors
do have a T cell receptor that could recognize something earlier in
the development of the tumor, but that the specific antigen on the
tumor itself has gradually been lost, as one of the many mechanisms
of the tumor to avoid recognition and destruction by the immune
Possibilities for further research
With this new method to determine the recognition capacity of a
T cell, immunologists can now zoom in on these tumor-specific T
cells, for example, to better understand their biology or to use
their tumor-specific receptor for the development of new forms of
Wouter Scheper et al., ´
Low and variable tumor reactivity of the intratumoral TCR
repertoire in human cancers', Nature Medicine,
December 3, 2018, doi.org/10.1038/s41591-018-0266-5.
This research was funded by KWF, EU Horizon 2020 and the K.G.