TREM2

TREM2 (Triggering receptor expressed on myeloid cells 2)

一行要約

TREM2 (6p21.1、HGNC:17761) は myeloid 細胞特異的に発現する Ig superfamily transmembrane receptor で、DAP12 (TYROBP) を ITAM adapter として SYK-PI3K-AKT / MAPK signaling を駆動する。腫瘍微小環境では TREM2+ tumor-associated macrophage (TAM) が免疫抑制的 / pro-tumorigenic な lipid-associated macrophage (LAM) phenotype を呈し、CD8+ T 細胞排除・線維化促進・抗 PD-1 抵抗性に寄与する pan-cancer macrophage checkpoint として確立しつつある。Mestrallet ら (Mestrallet et al. CellRepMed 2026) は MMRd/MMRp CRC で anti-TREM2 + anti-PD-1 + anti-LAG3 + anti-CTLA4 の 4 剤併用 が MMRd 100% / MMRp 73% の完全奏効を達成し、TREM2 を ICB 抵抗性克服の myeloid checkpoint として位置づけた。

主要エビデンス

• TREM2+ TAM の pan-cancer 同定: Molgora 2020 (Cell)・Katzenelenbogen 2020 (Cell) の同時報告で、TREM2+ macrophage が CD8 dysfunction と相関する pan-cancer 免疫抑制 macrophage subset として確立。Trem2 KO で B16 / MCA1956 で anti-PD-1 感受性が回復
• 4-checkpoint reprogramming Mestrallet et al. CellRepMed 2026: TREM2+CSF1R+ macrophage と多重 exhausted T 細胞 (PD-1+LAG3+CTLA4+) の三層耐性に対し、4 剤併用が MHC+C1Q+ macrophage (anti-tumor) と TCF+ stem-like T 細胞の境界共局在を再構築。Spatial transcriptomics ベースの machine learning で 87.5% 応答予測
• 抗 TREM2 抗体の臨床開発: PY314 (Pionyr) / AL002 (Alector、本来は AD adjuvant) が腫瘍領域でも検討。固形腫瘍 Phase 1 で T 細胞浸潤増加が報告
• 線維化との関連: 肝 NASH / 肺 IPF でも TREM2+ lipid-associated macrophage が pathogenic、TGF-β / efferocytosis を介した間質 remodeling driver

メカニズム

• 受容体 / ligand: DAP12 (TYROBP) を ITAM adapter として複合体形成。Ligand は多様 (anionic lipids / phosphatidylserine / β-amyloid / apolipoprotein E / DAMP)。Efferocytosis (apoptotic cell の貪食) を主要に媒介
• 下流 signaling: SYK → PI3K-AKT (survival / lipid metabolism) / MAPK / mTOR → lipid-associated macrophage (LAM) program (LPL, GPNMB, CD9 高発現)
• 免疫抑制機構:
• CD8+ T 細胞排除 (CCL chemokine 産生抑制 / spatial exclusion)
• Treg リクルート (CCL22 産生)
• Efferocytosis-mediated M2 polarization → IL-10 / TGF-β 産生
• PD-L1 upregulation
• 線維化・組織 remodeling: TGF-β 産生・collagen deposition の myCAF crosstalk → tumor stiffness / immune exclusion 強化

臨床位置づけ

TREM2 は CSF1R / CCR2 と並ぶ myeloid checkpoint の代表として位置づけられ、抗 PD-(L)1 単剤無効腫瘍 (PDAC / CRC MMRp / NSCLC cold tumor) での併用 partner として開発が進む。Mestrallet et al. CellRepMed 2026 の 4 剤併用は前臨床で MMRp CRC を 73% CR まで持ち込んだ画期的結果だが、ヒト irAE プロファイル (特に肝・神経学的、TREM2 は brain microglia でも発現) が未知であり、Phase 1 での dose-finding が課題。Spatial TLS マッピングを predictive biomarker に組み込む方向。

Open Questions

• 抗 TREM2 単剤 vs 併用の最適化: anti-PD-1 単剤 → anti-TREM2 add-on か、初手から多剤併用か
• 腫瘍別の TREM2+ macrophage subtype 差: lipid-associated LAM / SPP1+ TAM / FOLR2+ tissue-resident との overlap と機能差
• CNS irAE リスク: microglia TREM2 を抑制することによる神経炎症 / 認知機能影響
• Predictive biomarker: 血漿 sTREM2 / 腫瘍 IHC / spatial transcriptomic signature の標準化
• Efferocytosis 阻害の double-edged 効果: anti-tumor efferocytosis 阻害 vs autoimmune-prone な necrotic debris 蓄積

関連エンティティ

• 関連経路: PD-1-PD-L1-signaling-pathway / Phagocytosis-checkpoint-pathway / Neutrophil-recruitment-activation-pathway / TGF-beta-pathway
• 関連遺伝子: SPP1 (LAM marker overlap) / CSF1R (要確認) / STAT3
• 関連薬剤: PD-1-inhibitor / CTLA-4-inhibitor / LAG-3-inhibitor
• 関連細胞種: Macrophage-TAM / MDSC / Microglia / Exhausted-CD8-T-cell
• 関連概念: IO-primary-resistance / IO-acquired-resistance / Immune-checkpoint-beyond-PD1 / Tumor-immune-microenvironment-classification

関連論文

Basic-Brain metastasis

• Guldner et al. Cell 2020 — CNS-native myeloid cells drive immune suppression in the brain metastatic niche through Cxcl10

Basic-Immunotherapy

• Lavin et al. Cell 2017 — Innate immune landscape in early lung adenocarcinoma by paired single-cell analyses
• Wang et al. NatCellBiol 2026 — Slc2a1+ tumour-associated macrophages spatially control cd8+ t cell function and drive resistance to immunotherapy in

Basic-Neutrophil and myeloid cell

• Kloosterman et al. Cell 2023 — Macrophages at the interface of the co-evolving cancer ecosystem
• Mestrallet et al. CellRepMed 2026 — Reprogramming t cell-myeloid crosstalk overcomes immune resistance in colorectal cancer
• Aegerter et al. Immunity 2022 — Biology of lung macrophages in health and disease
• Nogales-Pons et al. JExpMed 2021 — Myeloid diversity in tumors shaped by genes, location, and time
• Redavid et al. JImmunotherCancer 2026 — Targeting macrophage-driven NK cell immunosuppression to improve cancer immunotherapy
• Salladay-Perez et al. NatAging 2026 — P21+trem2+ senescent macrophages fuel inflammaging and metabolic dysfunction-associated steatotic liver disease
• Chang et al. NatBiomedEng 2026 — CAR-neutrophils produced in vivo to treat glioma
• Boesch et al. NatGenet 2026 — Integrated multi-omics identifies distinct macrophage alterations during progression of metabolic
• Rys et al. TrendsCellBiol 2025 — Senescent neutrophils a hidden role in cancer progression

Basic-Others

• Tzouanas et al. Cell 2026 — Hepatic adaptation to chronic metabolic stress primes tumorigenesis
• Sharp et al. FrontImmunol 2023 — Experimental procedures for flow cytometry of wild-type mouse brain a systematic review
• Bojmar et al. NatMed 2024 — Multi-parametric atlas of the pre-metastatic liver for prediction of metastatic outcome in early-stage pancreatic cancer
• Ding et al. NatMed 2026 — Plasma proteomic signatures of cellular aging predict human disease
• Monroe et al. NatRevDrugDiscov 2026 — Therapeutic targeting of neuroimmune mechanisms in neurodegeneration
• Lee et al. NatRevImmunol 2026 — Glial cells in chronic inflammation diversity, dysfunction and therapeutic targeting
• Western et al. SciTranslMed 2026 — Low overlap of plasma and CSF protein quantitative trait loci affects protein discovery for neurological disease

Basic-Tumor microenvironment

• DeZuani et al. NatCommun 2024 — Single-cell and spatial transcriptomics analysis of non-small cell lung cancer
• Zhang et al. Nature 2026 — Non-invasive profiling of the tumour microenvironment with spatial ecotypes

Clinical-Others

• Lombardi et al. JHepatol 2026 — A myeloid immunosuppressive phenotype defines primary refractoriness to atezolizumab plus bevacizumab in hepatocellular

Clinical-Respiratory diseases

• Matralis et al. CellRepMed 2026 — An aerosolized dual-action autotaxin inhibitor-PPARgamma agonist for the treatment of pulmonary fibrosis