New Lung Immuno-oncology Therapeutic Strategy Identified
Pre-clinical study suggests that blocking a molecule while boosting a cell may reduce tumor growth in patients
Denoted in red, with tumor cells illuminated in green, TREM2 macrophages heavily infiltrate and occupy lung cancer lesions. Art Credit: Park et al., Nature Immunology
Researchers at the Icahn School of Medicine at Mount Sinai have demonstrated in a preclinical study a potential new therapeutic approach to treating the most common form of lung cancer.
The strategy involves inhibiting the immune-system molecule TREM2 while enhancing natural killer cells (the so-called protectors of the immune system). It was described in the April 20 online issue of Nature Immunology [DOI: 10.1038/s41590-023-01475-4]
https://www.nature.com/articles/s41590-023-01475-4.
“Our study reveals that macrophages expressing the molecule TREM2 drive the depletion and dysfunction of effector immune cells called natural killer cells, known to play a key role in the elimination of cancer cells, providing a strong rationale for the clinical development of combination therapies that concurrently block TREM2 and boost natural killer cells,” said first author Matthew Park, an MD/PhD candidate in the lab of Miriam Merad, MD, PhD, senior author of the study.
Dr. Merad is Director of the Precision Immunology Institute and Director of the Human Immune Monitoring Center at Icahn Mount Sinai.
Previous research has shown that many tumors from patients with non-small-cell lung cancer—the most common type, accounting for 85 percent of all lung cancers—and other cancers are deprived of these natural killer cells, which ordinarily have an innate ability to destroy cancer cells. In recent years, experts have made significant progress in understanding how tumors evade these cells when they are present. However, it remains unclear why these cells are absent from the tumors in the first place, according to the investigators.
In the current study, macrophages, another type of immune cell, were identified as the culprit. During tumor progression, the researchers found that bone marrow macrophages act to suppress the recruitment and activation of natural killer cells.
To learn why these macrophages have this effect, the research team performed sequencing to determine what genes may be at play, implicating the TREM2 molecule as highly expressed.
Finally, they discovered that inhibiting TREM2 activity using either mice with this mutation or blocking it from binding with an antibody significantly reduced lung tumor growth in mice.
“We identified a novel axis of immunity, whereby TREM2-expressing macrophages regulate the recruitment and activity of natural killer cells during lung tumor progression, and showed preclinical evidence for a new therapeutic strategy that combines TREM2 blockade and natural killer cell activation using an antibody developed by Dr. Ferrari de Andrade,” said Dr. Merad.
Lucas Ferrari de Andrade, PhD, a co-author of the paper, is Assistant Professor of Oncological Sciences at Icahn Mount Sinai. He is a member of the Precision Immunology Institute and the Tisch Cancer Center.
The researchers caution that although TREM2-expressing bone marrow-derived macrophages have been implicated in other tumor types, recent studies suggest TREM2 inhibition is not universally therapeutic. The Icahn Mount Sinai researchers intend to elucidate the applicability of this axis of immunity in other cancers.
The paper is titled, “TREM2 macrophages drive NK cell paucity and dysfunction in lung cancer.” To view the full list of authors, sources of funding, and competing interests, please see https://www.nature.com/articles/s41590-023-01475-4.
About the Icahn School of Medicine at Mount Sinai
The Icahn School of Medicine at Mount Sinai is internationally renowned for its outstanding research, educational, and clinical care programs. It is the sole academic partner for the eight member hospitals* of the Mount Sinai Health System, one of the largest academic health systems in the United States, providing care to a large and diverse patient population.
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Mount Sinai Health System is one of the largest academic medical systems in the New York metro area, with 48,000 employees working across eight hospitals, more than 400 outpatient practices, more than 600 research and clinical labs, a school of nursing, and a leading school of medicine and graduate education. Mount Sinai advances health for all people, everywhere, by taking on the most complex health care challenges of our time—discovering and applying new scientific learning and knowledge; developing safer, more effective treatments; educating the next generation of medical leaders and innovators; and supporting local communities by delivering high-quality care to all who need it.
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