New insights into how tumors metabolically adapt to their environment
may lead to better cancer therapies
The NAD+ biosynthetic pathway drives immunosuppression in high-grade
serous ovarian cancer
Date:
March 16, 2022
Source:
University of Chicago Medical Center
Summary:
A research team has discovered novel 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.
FULL STORY ========================================================================== High-grade serous carcinoma is the most aggressive form of ovarian cancer
and accounts for the majority of advanced-stage cases. The poor outcomes associated with the disease underscore the need for more effective
treatments. A research team led by Kunle Odunsi, MD, PhD, director of
the University of Chicago Medicine Comprehensive Cancer Center, has
discovered novel 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, as reported
in a paper published March 16, 2022, in Science Translational Medicine.
==========================================================================
Over the past several years, investigators from the University of Chicago, Roswell Park Comprehensive Cancer Center and other leading institutions
have teamed up to address one of the most pressing questions that
stymies breakthroughs in the treatment for ovarian cancer -- why does immunotherapy for ovarian cancer often fail? More specifically, they
explored the underlying mechanisms that result in tumors being able to
evade destruction by the immune system.
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 tumor
environment. Because tumors have realized that T cells are critically
dependent on tryptophan for their survival, the tumors make high amounts
of IDO1 in order 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 tumor shut off. Paradoxically, 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 goes on in the tumor microenvironment (TME) -- the surrounding normal cells, molecules,
and blood vessels that support a tumor's growth -- 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 tumor.
In the laboratory, they ran experiments to study the effects of EPA
on the TME from multiple angles. Their analyses 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 tumor 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- tumor activity by T
cells. The finding that NAD+, a component of key metabolism pathways,
affects immune responses opens a new window for understanding anti-
tumor immune responses.
The next question was how to use this information to improve therapy for patients with ovarian cancer. The researchers had a hunch. Because NAD+ metabolites could bind to purinergic receptors that communicate with the
immune system, they investigated the impact of blocking these receptors
on T cell proliferation and function in a mouse model of ovarian cancer.
The results were fascinating. 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 preclinical mouse model of ovarian cancer. Together they deliver
a one-two punch to increase anti-tumor activity.
"These findings highlight the potential downside of IDO1 inhibition and
suggest that IDO1 inhibitor therapy will require a combination with NAD+ signaling blockade," said Odunsi, lead author of the study.
The study is a prime example of translational research, which involves
taking observations from the clinic and studying them in the lab to
uncover vulnerable therapeutic targets. Also, the study illustrates the advantages of the team science approach, whereby a group of diverse
researchers working together could lead to more breakthroughs faster
than any one researcher working alone.
"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 characterization and visualization, and a preclinical model of ovarian
cancer," he said. "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."
========================================================================== Story Source: Materials provided by
University_of_Chicago_Medical_Center. Original written by Jane
Kollmer. Note: Content may be edited for style and length.
========================================================================== Journal Reference:
1. Kunle Odunsi, Feng Qian, Amit A. Lugade, Han Yu, Melissa A. Geller,
Steven P. Fling, Judith C. Kaiser, Andreanne M. Lacroix, Leonard
D'Amico, Nirasha Ramchurren, Chihiro Morishima, Mary L. Disis,
Lucas Dennis, Patrick Danaher, Sarah Warren, Van Anh Nguyen,
Sudharshan Ravi, Takemasa Tsuji, Spencer Rosario, Wenjuan
Zha, Alan Hutson, Song Liu, Shashikant Lele, Emese Zsiros,
A. J. Robert McGray, Jessie Chiello, Richard Koya, Thinle
Chodon, Carl D. Morrison, Vasanta Putluri, Nagireddy Putluri,
Donald E. Mager, Rudiyanto Gunawan, Martin A. Cheever, Sebastiano
Battaglia, Junko Matsuzaki. Metabolic adaptation of ovarian tumors
in patients treated with an IDO1 inhibitor constrains antitumor
immune responses. Science Translational Medicine, 2022; 14 (636)
DOI: 10.1126/ scitranslmed.abg8402 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/03/220316145827.htm
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