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Gajewski is
Abbvie Foundation Professor of Cancer Immunotherapy in the Ben
May Department for Cancer Research and Professor of Pathology and
Medicine at the University of Chicago, where he has worked for
more than two decades furthering understanding of fundamental
aspects of anti-tumour immunity and translating this into new
treatment strategies.
Immunotherapy represents a huge breakthrough for many cancer
patients, effectively ‘taking the brakes’ off the body’s immune
system so that T cells can detect and attack tumour cells. But
some patients don’t respond to immunotherapy and Gajewski
focussed on finding out why. To do this he explored the tumour
microenvironment – the immune cells, stroma, and the tumour cells
themselves – to tease out how this influences tumour responses to
the immune system.
“Many of us have been doing research in the field of cancer
immunotherapy for over 20 years, and it is amazing to see the
progress that is currently benefiting so many patients. It is
humbling to be recognised as perhaps representative of this
group, and especially by my European colleagues,” said Gajewski.
Looking to the future, Gajewski said, “Our view is that the
clinical benefit of checkpoint blockade immunotherapy will hit a
plateau, so understanding mechanisms of resistance or failure of
the current approaches is necessary to expand efficacy further.”
He concluded, “Studying secondary mechanisms of resistance is
already leading to new pathways and candidate targets.”
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Gajewski’s
research group found that patients whose T cells recognise tumour
cells have what they called a ‘hot’ or ‘T cell inflamed’ tumour
microenvironment. These T cells are suppressed but can fight
cancer cells if supported by immunotherapies. In contrast, other
patients have ‘cold’ tumours that lack T cells, making them
unresponsive to immunotherapy. The next step was to find out
how to give T cells access to these ‘cold’ tumour cells.
The group identified a protein complex called
STING (STimulator of INterferon Genes) that reacts to DNA that is
damaged or has drifted outside the cell nucleus. This helps to
alert the immune system that something is wrong, recruiting T
cells into the area. The discovery led to the development of
STING agonists that proved remarkably effective in laboratory
models of cancer and clinical trials of STING agonists are now
underway.
Gajweski and co-researchers also found that ‘cold’
tumour cells cloak themselves from T cells by expressing active
beta-catenin, an intracellular messenger (4,5). This prevents the
entry of dendritic cells, frontline soldiers in the immune system
that help to recruit T cells to the tumour site. The group is now
using this understanding to develop new therapeutic approaches.
A further major breakthrough was the finding that
the presence of certain types of ‘good’ bacteria in the gut
flora, the microorganisms colonising the intestines, can improve
the response to immunotherapy. The presence of these bacteria
appeared to increase T-cell infiltration into the tumour
environment, switching the tumour cells from ‘cold’ to ‘hot’ and
boosting the response to immunotherapy in patients being treated
for advanced melanoma.
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