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News

04Dec 2018

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Only a small proportion of T-cells recognize the tumor

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 Oncode.)

Immunotherapy

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 capacity

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 now.
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 donors.
'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 tumor?

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 system.'

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 immunotherapy. 

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. Jebsen Foundation.

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