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Published on: May 21, 2018
TREM2 macrophages drive NK cell paucity and dysfunction in lung cancer
Matthew D Park1,2,3, Ivan Reyes-Torres1,2,3, Jessica LeBerichel1,2,3
1Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Abstract:
Natural killer (NK) cells are commonly reduced in human tumors, enabling many to evade surveillance. Here, we sought to identify cues that alter NK cell activity in tumors. We found that, in human lung cancer, the presence of NK cells inversely correlated with that of monocyte-derived macrophages (mo-macs). In a murine model of lung adenocarcinoma, we show that engulfment of tumor debris by mo-macs triggers a pro-tumorigenic program governed by triggering receptor expressed on myeloid cells 2 (TREM2). Genetic deletion of Trem2 rescued NK cell accumulation and enabled an NK cell-mediated regression of lung tumors. TREM2+ mo-macs reduced NK cell activity by modulating interleukin (IL)-18/IL-18BP decoy interactions and IL-15 production. Notably, TREM2 blockade synergized with an NK cell-activating agent to further inhibit tumor growth. Altogether, our findings identify a new axis, in which TREM2+ mo-macs suppress NK cell accumulation and cytolytic activity. Dual targeting of macrophages and NK cells represents a new strategy to boost antitumor immunity.
Insights
Tumor-associated macrophages suppress natural killer (NK) cells via TREM2 signaling. Blocking this pathway enhances NK cell activity and promotes tumor regression, suggesting dual targeting for cancer immunotherapy.
Area of Science:
- Immunology
- Cancer Biology
- Tumor Microenvironment
Background:
- Natural killer (NK) cells are crucial for tumor surveillance but are often depleted in the tumor microenvironment.
- Monocyte-derived macrophages (mo-macs) are frequently found in tumors and can influence immune cell activity.
Purpose of the Study:
- To identify factors within the tumor microenvironment that modulate NK cell activity.
- To investigate the role of monocyte-derived macrophages (mo-macs) in suppressing NK cell function in lung cancer.
Main Methods:
- Analysis of NK cell and mo-mac correlation in human lung cancer samples.
- Utilized a murine model of lung adenocarcinoma.
- Investigated the role of triggering receptor expressed on myeloid cells 2 (TREM2) in mo-macs and its impact on NK cells.
- Assessed the effects of genetic deletion of Trem2 and TREM2 blockade on tumor growth and NK cell activity.
Main Results:
- A negative correlation was observed between NK cells and mo-macs in human lung cancer.
- Engulfment of tumor debris by TREM2+ mo-macs induced a pro-tumorigenic program in a murine lung adenocarcinoma model.
- Genetic deletion of Trem2 led to NK cell accumulation and tumor regression.
- TREM2+ mo-macs suppressed NK cell activity by altering IL-18/IL-18BP interactions and IL-15 production.
- TREM2 blockade combined with an NK cell activator inhibited tumor growth.
Conclusions:
- A novel axis involving TREM2+ mo-macs suppressing NK cell accumulation and cytolytic activity was identified.
- Targeting both macrophages and NK cells presents a promising strategy for enhancing antitumor immunity.
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