Targeting TREM2 on tumor-associated macrophages enhances immunotherapy

Cell Rep. 2021 Oct 19;37(3):109844. doi: 10.1016/j.celrep.2021.109844.

Abstract

Converting checkpoint inhibitor (CPI)-resistant individuals to being responsive requires identifying suppressive mechanisms. We identify TREM2+ tumor-associated macrophages (TAMs) as being correlated with exhausted CD8+ tumor-infiltrating lymphocytes (TILs) in mouse syngeneic tumor models and human solid tumors of multiple histological types. Fc domain-enhanced anti-TREM2 monoclonal antibody (mAb) therapy promotes anti-tumor immunity by elimination and modulation of TAM populations, which leads to enhanced CD8+ TIL infiltration and effector function. TREM2+ TAMs are most enriched in individuals with ovarian cancer, where TREM2 expression corresponds to disease grade accompanied by worse recurrence-free survival. In an aggressive orthotopic ovarian cancer model, anti-TREM2 mAb therapy drives potent anti-tumor immunity. These results highlight TREM2 as a highly attractive target for immunotherapy modulation in individuals who are refractory to CPI therapy and likely have a TAM-rich tumor microenvironment.

Trial registration: ClinicalTrials.gov NCT04691375.

Keywords: TAM; TREM2; afucosylation; checkpoint; exhaustion; glycoengineering; immunosuppression; immunotherapy; microenvironment; tumor-associated macrophages.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Immunological / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Line, Tumor
  • Coculture Techniques
  • Drug Resistance, Neoplasm
  • Female
  • HEK293 Cells
  • Humans
  • Immune Checkpoint Inhibitors / pharmacology*
  • Lymphocyte Activation / drug effects
  • Lymphocytes, Tumor-Infiltrating / drug effects
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • Membrane Glycoproteins / antagonists & inhibitors*
  • Membrane Glycoproteins / metabolism
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Neoplasms / drug therapy*
  • Neoplasms / immunology
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor / immunology
  • Programmed Cell Death 1 Receptor / metabolism
  • Receptors, Immunologic / antagonists & inhibitors*
  • Receptors, Immunologic / metabolism
  • Signal Transduction
  • Tumor Cells, Cultured
  • Tumor Microenvironment
  • Tumor-Associated Macrophages / drug effects*
  • Tumor-Associated Macrophages / immunology
  • Tumor-Associated Macrophages / metabolism

Substances

  • Antineoplastic Agents, Immunological
  • Immune Checkpoint Inhibitors
  • Membrane Glycoproteins
  • PDCD1 protein, human
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Receptors, Immunologic
  • TREM2 protein, human
  • Trem2 protein, mouse

Associated data

  • ClinicalTrials.gov/NCT04691375