TREM2 mediates MHCII-associated CD4+ T-cell response against gliomas

Neuro Oncol. 2024 May 3;26(5):811-825. doi: 10.1093/neuonc/noad214.

Abstract

Background: Myeloid cells comprise up to 50% of the total tumor mass in glioblastoma (GBM) and have been implicated in promoting tumor progression and immunosuppression. Modulating the response of myeloid cells to the tumor has emerged as a promising new approach for cancer treatment. In this regard, we focus on the Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), which has recently emerged as a novel immune modulator in peripheral tumors.

Methods: We studied the TREM2 expression profile in various patient tumor samples and conducted single-cell transcriptomic analysis in both GBM patients and the GL261 mouse glioma model. We utilized multiple mouse glioma models and employed state-of-the-art techniques such as invivo 2-photon imaging, spectrum flow cytometry, and in vitro co-culture assays to study TREM2 function in myeloid cell-mediated phagocytosis of tumor cells, antigen presentation, and response of CD4+ T cells within the tumor hemispheres.

Results: Our research revealed significantly elevated levels of TREM2 expression in brain tumors compared to other types of tumors in patients. TREM2 was predominantly localized in tumor-associated myeloid cells and was highly expressed in nearly all microglia, as well as various subtypes of macrophages. Surprisingly, in preclinical glioma models, TREM2 deficiency did not confer a beneficial effect; instead, it accelerated glioma progression. Through detailed investigations, we determined that TREM2 deficiency impaired the ability of tumor-myeloid cells to phagocytose tumor cells and led to reduced expression of MHCII. This deficiency further significantly decreased the presence of CD4+ T cells within the tumor hemispheres.

Conclusions: Our study unveiled a previously unrecognized protective role of tumor-myeloid TREM2. Specifically, we found that TREM2 enhances the phagocytosis of tumor cells and promotes an immune response by facilitating MHCII-associated CD4+ T-cell responses against gliomas.

Keywords: TREM2; glioma; tumor-associated macrophages.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Brain Neoplasms* / immunology
  • Brain Neoplasms* / metabolism
  • Brain Neoplasms* / pathology
  • CD4-Positive T-Lymphocytes* / immunology
  • CD4-Positive T-Lymphocytes* / metabolism
  • Glioma* / genetics
  • Glioma* / immunology
  • Glioma* / metabolism
  • Glioma* / pathology
  • Histocompatibility Antigens Class II / metabolism
  • Humans
  • Membrane Glycoproteins* / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Phagocytosis
  • Receptors, Immunologic* / metabolism
  • Tumor Cells, Cultured

Substances

  • Receptors, Immunologic
  • Membrane Glycoproteins
  • TREM2 protein, human
  • Trem2 protein, mouse
  • Histocompatibility Antigens Class II