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 Hamel; Alfonso 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

doi:10.1038/s41590-023-01475-4

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 journal › Article › peer-review

80 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 language	English
Pages (from-to)	792-801
Number of pages	10
Journal	Nature immunology
Volume	24
Issue number	5
DOIs	https://doi.org/10.1038/s41590-023-01475-4
State	Published - May 2023

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Park, M. D., Reyes-Torres, I., LeBerichel, J., Hamon, P., LaMarche, N. M., Hegde, S., Belabed, M., Troncoso, L., Grout, J. A., Magen, A., Humblin, E., Nair, A., Molgora, M., Hou, J., Newman, J. H., Farkas, A. M., Leader, A. M., Dawson, T., D’Souza, D., ... Merad, M. (2023). TREM2 macrophages drive NK cell paucity and dysfunction in lung cancer. Nature immunology, 24(5), 792-801. https://doi.org/10.1038/s41590-023-01475-4

@article{32e935e1708a4b0a831ee14c5e25b23f,

title = "TREM2 macrophages drive NK cell paucity and dysfunction in lung cancer",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2023",

month = may,

doi = "10.1038/s41590-023-01475-4",

language = "English",

volume = "24",

pages = "792--801",

journal = "Nature immunology",

issn = "1529-2908",

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Park, MD, Reyes-Torres, I, LeBerichel, J, Hamon, P, LaMarche, NM, Hegde, S, Belabed, M, Troncoso, L, Grout, JA, Magen, A, Humblin, E, Nair, A, Molgora, M, Hou, J, Newman, JH, Farkas, AM, Leader, AM, Dawson, T, D’Souza, D, Hamel, S, Sanchez-Paulete, AR, Maier, B, Bhardwaj, N, Martin, JC, Kamphorst, AO, Kenigsberg, E, Casanova-Acebes, M, Horowitz, A, Brown, BD, De Andrade, LF, Colonna, M, Marron, TU & Merad, M 2023, 'TREM2 macrophages drive NK cell paucity and dysfunction in lung cancer', Nature immunology, vol. 24, no. 5, pp. 792-801. https://doi.org/10.1038/s41590-023-01475-4

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T1 - TREM2 macrophages drive NK cell paucity and dysfunction in lung cancer

AU - Park, Matthew D.

AU - Reyes-Torres, Ivan

AU - LeBerichel, Jessica

AU - Hamon, Pauline

AU - LaMarche, Nelson M.

AU - Hegde, Samarth

AU - Belabed, Meriem

AU - Troncoso, Leanna

AU - Grout, John A.

AU - Magen, Assaf

AU - Humblin, Etienne

AU - Nair, Achuth

AU - Molgora, Martina

AU - Hou, Jinchao

AU - Newman, Jenna H.

AU - Farkas, Adam M.

AU - Leader, Andrew M.

AU - Dawson, Travis

AU - D’Souza, Darwin

AU - Hamel, Steven

AU - Sanchez-Paulete, Alfonso Rodriguez

AU - Maier, Barbara

AU - Bhardwaj, Nina

AU - Martin, Jerome C.

AU - Kamphorst, Alice O.

AU - Kenigsberg, Ephraim

AU - Casanova-Acebes, Maria

AU - Horowitz, Amir

AU - Brown, Brian D.

AU - De Andrade, Lucas Ferrari

AU - Colonna, Marco

AU - Marron, Thomas U.

AU - Merad, Miriam

PY - 2023/5

Y1 - 2023/5

N2 - 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.

AB - 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.

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DO - 10.1038/s41590-023-01475-4

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JO - Nature immunology

JF - Nature immunology

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ER -

TREM2 macrophages drive NK cell paucity and dysfunction in lung cancer

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