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.

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.

Ranked 14th nationwide in National Institutes of Health (NIH) funding and among the 99th percentile in research dollars per investigator according to the Association of American Medical Colleges, Icahn Mount Sinai has a talented, productive, and successful faculty. More than 3,000 full-time scientists, educators, and clinicians work within and across 34 academic departments and 35 multidisciplinary institutes, a structure that facilitates tremendous collaboration and synergy. Our emphasis on translational research and therapeutics is evident in such diverse areas as genomics/big data, virology, neuroscience, cardiology, geriatrics, as well as gastrointestinal and liver diseases.

Icahn Mount Sinai offers highly competitive MD, PhD, and Master’s degree programs, with current enrollment of approximately 1,300 students. It has the largest graduate medical education program in the country, with more than 2,000 clinical residents and fellows training throughout the Health System. In addition, more than 550 postdoctoral research fellows are in training within the Health System.

A culture of innovation and discovery permeates every Icahn Mount Sinai program. Mount Sinai’s technology transfer office, one of the largest in the country, partners with faculty and trainees to pursue optimal commercialization of intellectual property to ensure that Mount Sinai discoveries and innovations translate into healthcare products and services that benefit the public.

Icahn Mount Sinai’s commitment to breakthrough science and clinical care is enhanced by academic affiliations that supplement and complement the School’s programs.

Through the Mount Sinai Innovation Partners (MSIP), the Health System facilitates the real-world application and commercialization of medical breakthroughs made at Mount Sinai. Additionally, MSIP develops research partnerships with industry leaders such as Merck & Co., AstraZeneca, Novo Nordisk, and others.

The Icahn School of Medicine at Mount Sinai is located in New York City on the border between the Upper East Side and East Harlem, and classroom teaching takes place on a campus facing Central Park. Icahn Mount Sinai’s location offers many opportunities to interact with and care for diverse communities. Learning extends well beyond the borders of our physical campus, to the eight hospitals of the Mount Sinai Health System, our academic affiliates, and globally.

* Mount Sinai Health System member hospitals: The Mount Sinai Hospital; Mount Sinai Beth Israel; Mount Sinai Brooklyn; Mount Sinai Morningside; Mount Sinai Queens; Mount Sinai South Nassau; Mount Sinai West; and New York Eye and Ear Infirmary of Mount Sinai.

Journal: Nature Immunology
DOI: 10.1038/s41590-023-01475-4
Method of Research: Experimental study
Subject of Research: Animals
Article Title: TREM2 macrophages drive NK cell paucity and dysfunction in lung cancer
Article Publication Date: 20-Apr-2023

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