TREM2 mediates MHC II-associated CD4+ T-cell response against gliomas
The human genome-encoded triggering receptor expressed on myeloid cells 2 (TREM2) was initially thought to play a role primarily in the central nervous system, participating in the functional regulation of microglia. In recent years, researchers have found that TREM2 is also expressed in peripheral tumors and may promote tumor progression. However, the specific role of TREM2 in brain tumors has remained unclear.
A recent study systematically analyzed the expression patterns and potential functions of TREM2 in glioblastoma multiforme (GBM) and other types of brain tumors. The study was led by Dr. Long-Jun Wu’s research group at the Mayo Clinic, and the results were recently published in the top journal Neuro-Oncology.
The researchers first found that the expression level of TREM2 in tumor tissues of brain tumor patients was significantly higher compared to other types of tumors. Single-cell transcriptome sequencing analysis revealed that TREM2 was highly expressed mainly in tumor-associated microglia and infiltrating macrophages. Interestingly, the expression level of TREM2 was positively correlated with genes associated with cell phagocytosis and antigen presentation, while the correlation with immunosuppressive genes was relatively low.
To further investigate the role of TREM2 in gliomas, the researchers constructed a TREM2-deficient mouse glioma model.
Surprisingly, compared to normal controls, the progression of gliomas in the TREM2-deficient mouse model was not slowed down but rather accelerated. Further research found that TREM2 deficiency led to a decrease in the phagocytic ability of tumor-associated myeloid cells towards tumor cells and a reduction in the surface expression level of MHC II molecules.
MHC II molecules are involved in the presentation of exogenous antigens, thereby activating CD4+ helper T cells. A series of in vivo and in vitro experiments further confirmed that TREM2 deficiency inhibited the infiltration and activation of CD4+ T cells in the tumor microenvironment. Clinical data analysis also supported a positive correlation between TREM2 and the Th1-type CD4+ T cell IFN-γ signaling pathway in brain tumors.
Overall, this study revealed a novel mechanism by which TREM2 promotes brain tumor progression: TREM2 can enhance the ability of myeloid cells to phagocytose tumor cell debris, thereby activating CD4+ T cell-mediated antitumor immune responses through the MHC II antigen presentation pathway. This finding not only deepens our understanding of the role of TREM2 in tumor immune regulation but also provides new insights for the future development of TREM2-targeted tumor immunotherapies.
The main highlights of this study include:
In human glioblastoma multiforme and mouse glioma models, TREM2 is highly expressed primarily in tumor-associated microglia and infiltrating macrophages.
The expression level of TREM2 is positively correlated with genes associated with cell phagocytosis and antigen presentation, while its correlation with immunosuppressive genes is relatively low.
In the mouse glioma model, TREM2 deficiency accelerated tumor progression and promoted tumor growth.
TREM2 deficiency reduced the phagocytic ability of tumor-associated myeloid cells towards tumor cell debris and decreased the surface expression of MHC II molecules.
In vivo and in vitro experimental results showed that TREM2 deficiency inhibited the infiltration and activation of CD4+ T cells in the tumor microenvironment.
Clinical data analysis found that the expression level of TREM2 was positively correlated with the IFN-γ signaling pathway of Th1-type CD4+ T cells in brain tumors.
The study revealed a new mechanism by which TREM2 suppresses brain tumor progression by promoting myeloid cell phagocytosis and MHC II-mediated CD4+ T cell activation.
This finding provides new insights for the future development of novel TREM2-targeted tumor immunotherapies.
This study has important implications for deepening our understanding of the mechanisms underlying TREM2’s role in tumor immune regulation and lays the foundation for the future development of TREM2-related tumor immunotherapies.