By investigating the behavior and looks of T cells
within the tumor microenvironment of non-small-cell lung cancer
patients, Netherlands Cancer Institute and Oncode
researchers Daniela Thommen and Ton Schumacher and colleagues from Basel may
have opened up a new venue for stratifying patients for cancer
Read their paper that was published in Nature Medicine on
June 11th 2018
Cancer immunotherapy is aimed at boosting the patient's own
immune system to fight cancer cells. Immunotherapy is now a
standard therapy for advanced-stage non-small cell lung cancer and
25% of the patients show - sometimes long-term - clinical responses
to this therapy. But why do these patients respond well whereas the
A better understanding of the differences between these patient
groups may allow clinicians to determine in advance which patients
are more likely to benefit from immunotherapy. Other patients may
then be better off with another type of treatment and will be
spared the side effects of immunotherapy. In addition, in
view of the high costs of cancer immunotherapy for lung cancer
(over 80% of all lung cancer is non-small cell lung cancer), it
would be of value to only treat those patients who can be expected
Daniela Thommen: 'But the most fundamental reason for studying
this is the following: the moment you understand why some patients
do not respond, you may try to solve the issue and treat a broader
range of patients.'
To answer this question, Thommen analyzed the T cells in tumor
biopsy material from a group of patients with stage 4 non-small
cell lung cancer and compared their properties with clinical
outcome. These patients, who were followed up to two years, were
treated with so-called checkpoint inhibitors (or PD-1 blockade).
This is now a broadly used form of cancer immunotherapy, aimed at
reinvigorating T cells (CD8+ T cells) that have lost their ability
to kill cancer cells.
Checkpoints and checkpoint inhibitors
Checkpoints are molecules on the surface of T cells that
regulate the immune response and prevent T cells from killing
innocent cells in the body. Cancer cells sometimes bind to these
checkpoints in order to avoid being attacked by T cells. Checkpoint
inhibitors are aimed at preventing cancer cells from doing
T cells scan the body, recognize deviant cells and kill them.
They do not only recognize cells infected by foreign intruders,
such as viruses, but also recognize cancer cells for a number of
human cancers, including non-small cell lung cancer.
It was already known that in chronic viral infections, T cells
differ in their functionality. Thommen: 'I wanted to know whether
this is also the case in cancer. And, if so, the next question
would be if this can help to identify patients who are likely to
respond to immunotherapy.'
The team discovered that the best way to differentiate between T
cells in non-small cell lung cancer is by looking at the number of
PD-1 checkpoint molecules on the cell surface. They saw that T
cells that are crowded with these checkpoints on their surface,
recognize the tumor cells best.
Moreover, in the cohort of non-small cell lung cancer patients,
the presence of these checkpoint-enriched T cells was strongly
predictive for both response and survival. 'The predictive
potential outperforms classical diagnostic tests in this patient
cohort', says Thommen.
This specific population of checkpoint-enriched T cells stood
out in a number of ways. Firstly, they were the only population of
T cells that could strongly recognize tumor cells. Secondly, on the
downside, they were the most dysfunctional T cell population in the
tumor, expressing a series of other checkpoints next to PD-1.
However, on the upside, they gained a new functionality in return,
recruiting new T cells to the tumor micro-environment.
'We don't really know what makes them do this', says Thommen.
'It may be something in the tumor. Or it may be lack of nutrients
at the tumor site. This is something we aim to further study in the
coming period. The researchers also intend to validate the value of
the most dysfunctional T cells as a biomarker for immunotherapy
response in an independent patient cohort. Finally, they intend to
study whether the T cells will flip back into their original
function upon treatment.
Daniela Thommen e.a., 'A transcriptionally and functionally distinct
PD-1+ CD8+ T cell pool with
predictive potential in non-small-cell lung cancer treated with
Nature Medicine online publication, 11 June
This work was supported by grants from the Swiss National Science
Foundation, the Research Funds University of Basel,the
Lichtenstein-Stiftung,the FAG-Basel,the Dutch Cancer Society and
the European Research Council.