New
research has discovered metabolic mechanisms that contribute to how ovarian
cancer escapes from immune attack and how combination therapies can exploit
these pathways to improve ovarian cancer treatment.
Researchers
at the University of Chicago Medicine Comprehensive Center, US have highlighted
new insights into how tumours metabolically adapt to their environment. The
study, which was recently published in Science Translational
Medicine, may lead to better cancer therapies — serous
carcinoma is the most aggressive form of ovarian cancer and accounts for most
advanced-stage cases. The poor outcomes associated with the disease emphasise
the need for more effective
treatments.
The researchers focused on targeting an enzyme called indoleamine
2,3-dioxygenase 1 (IDO1), which is responsible for degrading the amino acid
tryptophan, to generate break-down products that can suppress cancer-fighting
immune cells (T cells) within the tumour environment. Tumours
know that T cells are critically dependent on tryptophan for their survival,
therefore, the tumours make high amounts of IDO1 to deprive T cells of
tryptophan. Previous studies indicated that targeting the IDO1 pathway with a
drug that blocks its action, known as epacadostat (EPA), can switch back on the
T cells that the tumour shuts off. The researchers found, however, that IDO1
blockade in combination with immunotherapy has
shown limited success in clinical trials, indicating a gap in knowledge of IDO1
biology and the consequences of blocking it.
To better understand how ovarian cancer escapes from immune attack, the
research team wanted to see exactly what occurs in the tumour microenvironment
(TME) when IDO1 is blocked. Their search began in the clinic, where they
collected tissue samples from patients with newly diagnosed advanced ovarian
cancer who had not undergone surgery or chemotherapy. They collected samples
again after the patients received treatment with a two-week course of EPA and
surgery to remove the tumour.
In
the laboratory, they ran experiments to study the effects of EPA on the TME
from multiple angles. Their studies revealed EPA was effective at blocking the
IDO1 pathway of tryptophan degradation, but also revealed that this action
triggered a separate chain of events. The tumour microenvironment adapted to
these new conditions by redirecting the breakdown of tryptophan toward the
serotonin pathway and increasing production of nicotinamide adenine
dinucleotide (NAD+). The elevated NAD+ was the key culprit in reducing
anti-tumour activity by T cells. The finding that NAD+, a component of key
metabolism pathways, affects immune responses opens a new window for
understanding anti-tumour immune responses.
The researchers then aimed to find how they can use these results to
improve therapy for ovarian cancer patients. They believed that NAD+
metabolites could bind to purinergic receptors that communicate with the immune
system, therefore, they investigated the impact of blocking these receptors on
T-cell proliferation and function in a mouse model of ovarian cancer.
They found that the combination of IDO inhibition with EPA and an
antagonist drug designed to interfere with the purinergic receptors “rescued”
T-cell proliferation and led to improved survival in a pre-clinical mouse model
of ovarian cancer. Together they deliver a one-two punch to increase
anti-tumour activity.
“This work represents a highly collaborative effort spanning a broad
range of expertise using cutting-edge technologies, from clinical expertise to
statistics, metabolism, gene expression, advanced cell characterisation and
visualisation and a pre-clinical model of ovarian cancer,” concluded Dr Kunle
Odunsi, research lead. “This body of work encapsulates a tremendous amount of
effort, knowledge and expertise from a total of 36 researchers focused on
understanding how we can improve ovarian cancer immunotherapy.”
World Journal of Case Reports and Clinical Images (ISSN 2835-1568)
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