TREM2 macrophages drive NK cell paucity and dysfunction in lung cancer

Nat Immunol. 2023 May;24(5):792-801. doi: 10.1038/s41590-023-01475-4. Epub 2023 Apr 20.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Humans
  • Killer Cells, Natural*
  • Lung Neoplasms*
  • Macrophages
  • Membrane Glycoproteins / genetics
  • Mice
  • Myeloid Cells
  • Receptors, Immunologic / genetics


  • TREM2 protein, human
  • Membrane Glycoproteins
  • Receptors, Immunologic
  • Trem2 protein, mouse