TREM2巨噬细胞导致肺癌NK细胞缺乏和功能障碍

2023-05-08 09:22

自然杀伤（NK）细胞通常在人类肿瘤中减少，使许多肿瘤能够逃避监视。

SCI

7 May 2023

TREM2 macrophages drive NK cell paucity and dysfunction in lung cancer

(Nature immunology,IF:31.25)

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. 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. PMID: 37081148.

Corresponding author(s): Miriam Merad,MD,PHD,Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.e-mail: miriam.merad@mssm.edu

Abstract 摘要

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.

自然杀伤（NK）细胞通常在人类肿瘤中减少，使许多肿瘤能够逃避监视。在此，我们试图确定改变肿瘤中NK细胞活性的原因。我们发现，在人肺癌中，NK细胞的存在与单核细胞来源的巨噬细胞（mo-macs）呈负相关。在肺腺癌的小鼠模型中，我们发现mo-macs吞噬肿瘤碎片会触发受控于髓系细胞触发受体2（TREM2）的促肿瘤程序。Trem2基因缺失促进了NK细胞的积累，并使NK细胞介导的肺部肿瘤消退成为可能。TREM2+ mo-macs通过调节白细胞介素（IL）-18/IL-18BP诱饵相互作用和IL-15的产生来降低NK细胞活性。值得注意的是，TREM2阻断剂与NK细胞激活剂的协同作用能进一步抑制肿瘤生长。总之，我们的发现确定了一个新的调控通路，其中TREM2+ mo-macs抑制NK细胞积累和细胞溶解活性。同时靶向巨噬细胞和NK细胞是增强抗肿瘤免疫力的一种新策略。