NEW YORK, April 9, 2021 /PRNewswire-PRWeb/ -- Sets of genes
associated with resistance to immunotherapy in patients with
metastatic urothelial cancer of the bladder have been identified
and validated by researchers at Mount
Sinai. In a study published in Clinical Cancer Research, the
team uncovered gene signatures representing adaptive immunity and
pro-tumorigenic inflammation that were responsible for sensitivity
or resistance to immune checkpoint inhibitors, drugs that help the
body's immune system recognize and attack cancerous cells.
"These findings enabled us to identify potential biomarkers in
patients who are less likely to respond favorably to immune
checkpoint inhibitors, as well as new combination therapeutic
approaches that might overcome such resistance in those patients,"
says senior author Matthew Galsky,
MD, Professor of Medicine (Hematology and Medical Oncology), Icahn
School of Medicine at Mount
Sinai.
Significantly, the findings demonstrated that the balance
between adaptive immunity and pro-tumorigenic inflammation in
individual tumor microenvironments—reflected by these two gene
signatures—best predicted response or resistance to immune
checkpoint blockade. The researchers then identified specific cells
in the tumor microenvironment associated with resistance to immune
checkpoint blockade, and potential targets for therapies designed
to overcome resistance.
For decades, standard treatment for metastatic urothelial cancer
of the bladder has been platinum-based chemotherapy, though the
landscape has changed dramatically in recent years with the advent
of PD-1 and PD-L1 immune checkpoint inhibitors. This therapeutic
breakthrough has had its limits, though: only 20 to 25 percent of
patients with bladder cancer respond to treatment, which has set
off an intense hunt by biomedical scientists for mechanisms of
resistance.
"Using RNA sequencing data from two clinical trials, and single
cell RNA sequencing data from a cohort of bladder tumors, we
identified a subset of genes and immune cells associated with
adaptive immunity and improved checkpoint inhibitor outcomes, and a
subset associated with pro-tumorigenic inflammation and resistance
to PD-1/PD-L1 blockade in patients with urothelial cancer," Dr.
Galsky says.
The research is among the first to use both bulk and single-cell
RNA sequencing of human bladder tumors to study resistance to
immunotherapy. Bulk sequencing examines the mix of genes expressed
by every individual cell within a tumor, while single-cell
sequencing—a technique increasingly important in cancer
research—zeroes in on gene expression by each individual cell,
which yields unprecedented knowledge of the complexity and
heterogeneity of cells that comprise tumors.
Through this combination of RNA sequencing, researchers learned,
for example, that the balance of adaptive immunity and
pro-tumorigenic inflammation within the tumor microenvironment can
determine PD-1/PD-L1 resistance in urothelial cancer. Adaptive
immunity is the body's ability to recognize and respond to specific
foreign invaders, while pro-tumorigenic inflammation is a
counterproductive response of the immune system that can ultimately
fuel growth and progression of cancer.
"If the tumor microenvironment is weighted more toward adaptive
immunity, there's a better chance of positive outcomes from
immunotherapy," explains Dr. Galsky, who is Associate Director of
Translational Research and Co-Director of the Bladder Cancer Center
of Excellence at The Tisch Cancer Institute. "On the other hand, if
the tumor microenvironment is leaning toward pro-tumorigenic
inflammation, then PD-1/PD-L1 checkpoint inhibitors alone are
unlikely to be successful, and new combination approaches may be
needed." Mount Sinai researchers
coined the term "2IR Score" to measure that balance.
From its comprehensive RNA analysis, the team identified not
just potential biomarkers to treatment resistance, but a specific
subset of white blood cells known as myeloid phagocytic cells that
are linked to pro-tumorigenic inflammation and, hence, resistance.
As such, they serve as prospective targets for therapeutic
approaches that combine immunotherapies like PD-1/PD-L1 blockade
with drugs designed to overcome the resistance conferred by myeloid
cells. Those novel combination strategies are now being
incorporated into future clinical trials.
"Our research shows that a specific cellular state of myeloid
cells underlying pro-tumorigenic inflammation account for
resistance to immune checkpoint blockade in a very large percentage
of patients with urothelial bladder cancer," Dr. Galsky says. "This
is an important finding which we believe can lead to a better focus
and direction for developing effective combination therapies – and
not just for bladder cancer, but other types of tumors, as
well".
The Mount Sinai-led study was a
collaborative effort with Bristol-Myers Squibb and the University of Texas MD Anderson Cancer Center.
Research reported in the Clinical Cancer Research publication was
supported by the National Cancer Institute of the National
Institutes of Health (NIH) under Award Number R01CA249175. The
content is solely the responsibility of the authors and does not
necessarily represent the official views of the NIH.
About the Mount Sinai Health System
The Mount Sinai Health System is New
York City's largest academic medical system, encompassing
eight hospitals, a leading medical school, and a vast network of
ambulatory practices throughout the greater New York region. Mount Sinai is a national and international
source of unrivaled education, translational research and
discovery, and collaborative clinical leadership ensuring that we
deliver the highest quality care—from prevention to treatment of
the most serious and complex human diseases. The Health System
includes more than 7,200 physicians and features a robust and
continually expanding network of multispecialty services.
Media Contact
Marlene Naanes, Mount Sinai
Health System, 212-241-9200, marlene.naanes@mountsinai.org
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