@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 = "Funding Information: M.M. conceived the project. M.M., M.D.P. and I.R.T. wrote the manuscript. I.R.T., M.D.P. and M.M. designed the experiments. I.R.T., M.D.P., J.L.B., N.M.L., E.H., S.H., M.B., A.N. and A.R.S. performed experiments. I.R.T., M.D.P., J.L.B. and A.N. maintained mouse colonies and cell cultures for these experiments. M.D.P. and A.M. performed computational analyses, with additional support from T.D., D.D. and S.H. P.H., L.T. and J.G. provided immunohistochemistry stains and analyses. M.M., J.H. and M.C. provided the TREM2 blocking antibody and isotype control. J.N., A.F. and N.B. provided the IL-15 neutralizing antibody; M.J.L. and J.B. provided the antibodies against NKG2D ligands; and L.F.A. provided the MIC-A stabilizing antibody and B16-F10-MICA cell line. A.R.S., B.M., J.C.M., E.K., A.O.K., M.C.A., N.B., A.H., L.F.A., B.D.B., M.C. and T.U.M. provided intellectual input. This work was supported by National Institutes of Health grants R01 AI153363 (to A.O.K.), R01 CA254104 and R01 CA257195 (to M.M. and B.D.B.), 1R37 CA269982-01A1 (to L.F.d.A.), R01CA262684 to M.C. S.H. was supported by the National Cancer Institute predoctoral-to-postdoctoral fellowship K00 CA223043. N.M.L. was supported by the Cancer Research Institute/Bristol Myers Squibb Irvington Postdoctoral Research Fellowship to Promote Racial Diversity (award no. CRI3931). B.D.B. and M.M. were supported by the Applebaum Foundation and the Feldman Foundation. B.D.B. was supported by the Alliance for Cancer Gene Therapy. L.F.d.A. is the recipient of a Cancer Research Institute Clinic and Laboratory Integration Program Grant (award no. CRI3483), Tisch Cancer Institute Developments Funds Award (P30CA196521), Department of Defense Career Development Award (W81XWH2210262 and project number CA210940), Leukemia and Lymphoma Society (award no. 6647-23) and is supported by the Elsa U. Pardee Foundation. 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",
number = "5",
}