Macrophages suppress natural killer cells in lung cancer tumours

Natural killer cells

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.

“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, 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 tumours from patients with non-small-cell lung cancer and other cancers are deprived of these natural killer cells, but it remains unclear why.

In the current study, macrophages were identified as the culprit. During tumour progression, the researchers found that bone marrow macrophages act to suppress the recruitment and activation of natural killer cells.

TREM2-expressing macrophages

The research team performed sequencing to determine what genes may be at play, implicating the TREM2 molecule as highly expressed. They discovered that inhibiting TREM2 activity using either mice with this mutation or blocking it from binding with an antibody significantly reduced lung tumour 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 tumour 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, a co-author of the paper, is Assistant Professor of Oncological Sciences at Icahn Mount Sinai.

The researchers caution that although TREM2-expressing bone marrow-derived macrophages have been implicated in other tumour types, recent studies suggest TREM2 inhibition is not universally therapeutic.

Read the full paper: ‘TREM2 macrophages drive NK cell paucity and dysfunction in lung cancer’.

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