TREM2 macrophages drive NK cell paucity and dysfunction in lung cancer

Matthew D. Park, Ivan Reyes-Torres, Jessica LeBerichel, Pauline Hamon, Nelson M. LaMarche, Samarth Hegde, Meriem Belabed, Leanna Troncoso, John A. Grout, Assaf Magen, Etienne Humblin, Achuth Nair, Martina Molgora, Jinchao Hou, Jenna H. Newman, Adam M. Farkas, Andrew M. Leader, Travis Dawson, Darwin D’Souza, Steven HamelAlfonso Rodriguez Sanchez-Paulete, Barbara Maier, Nina Bhardwaj, Jerome C. Martin, Alice O. Kamphorst, Ephraim Kenigsberg, Maria Casanova-Acebes, Amir Horowitz, Brian D. Brown, Lucas Ferrari De Andrade, Marco Colonna, Thomas U. Marron, Miriam Merad

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

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.

Original languageEnglish
Pages (from-to)792-801
Number of pages10
JournalNature immunology
Volume24
Issue number5
DOIs
StatePublished - May 2023

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