2. Academic Validation
  3. TREM2 Modulation Remodels the Tumor Myeloid Landscape Enhancing Anti-PD-1 Immunotherapy

TREM2 Modulation Remodels the Tumor Myeloid Landscape Enhancing Anti-PD-1 Immunotherapy

  • Cell. 2020 Aug 20;182(4):886-900.e17. doi: 10.1016/j.cell.2020.07.013.
Martina Molgora 1,  Ekaterina Esaulova 1,  William Vermi 2,  Jinchao Hou 1,  Yun Chen 1,  Jingqin Luo 3,  Simone Brioschi 1,  Mattia Bugatti 4,  Andrea Salvatore Omodei 4,  Biancamaria Ricci 5,  Catrina Fronick 6,  Santosh K Panda 1,  Yoshiko Takeuchi 1,  Matthew M Gubin 7,  Roberta Faccio 8,  Marina Cella 1,  Susan Gilfillan 1,  Emil R Unanue 1,  Maxim N Artyomov 1,  Robert D Schreiber 9,  Marco Colonna 10
Affiliations

Affiliations

  • 1 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 2 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology, University of Brescia, Brescia 25123, Italy.
  • 3 Division of Public Health Sciences, Siteman Cancer Center Biostatistics Core, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 4 Department of Pathology, University of Brescia, Brescia 25123, Italy.
  • 5 Department of Orthopedics, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 6 McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63108, USA.
  • 7 Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 8 Department of Orthopedics, Washington University School of Medicine, St. Louis, MO 63110, USA; Shriners Children's Hospital in St. Louis, St. Louis, MO 63110, USA.
  • 9 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 10 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: [email protected].
PMID: 32783918 DOI: 10.1016/j.cell.2020.07.013
Abstract

Checkpoint immunotherapy unleashes T cell control of tumors, but is undermined by immunosuppressive myeloid cells. TREM2 is a myeloid receptor that transmits intracellular signals that sustain microglial responses during Alzheimer's disease. TREM2 is also expressed by tumor-infiltrating macrophages. Here, we found that Trem2-/- mice are more resistant to growth of various cancers than wild-type mice and are more responsive to anti-PD-1 immunotherapy. Furthermore, treatment with anti-TREM2 mAb curbed tumor growth and fostered regression when combined with anti-PD-1. scRNA-seq revealed that both TREM2 deletion and anti-TREM2 are associated with scant MRC1+ and CX3CR1+ macrophages in the tumor infiltrate, paralleled by expansion of myeloid subsets expressing immunostimulatory molecules that promote improved T cell responses. TREM2 was expressed in tumor macrophages in over 200 human Cancer cases and inversely correlated with prolonged survival for two types of Cancer. Thus, TREM2 might be targeted to modify tumor myeloid infiltrates and augment checkpoint immunotherapy.

Keywords

TREM2; breast cancer; checkpoint blockade; colorectal cancer; human; macrophages; sarcoma; tumor.

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