Isocitrate dehydrogenase mutation and microenvironment in gliomas: do immunotherapy approaches matter?

Gliomas with mutations in the gene for isocitrate dehydrogenase (IDH) display a unique immune microenvironment that is distinct from IDH-wildtype gliomas. This unique immune microenvironment is shaped by 2-hydroxyglutarate (2-HG), an oncometabolite produced by mutant IDH. These features provide an opportunity to develop and test targeted immunotherapies for IDH-mutant gliomas.

IDH-mutant gliomas are characterized by an immunosuppressive tumor immune microenvironment (TIME) that suppresses the infiltration and activation of tumor-specific T cells. This is owed both to direct effects of the oncometabolite 2-hydroxyglutarate on glioma-infiltrating T cells and myeloid cells and indirect effects on the chemotactic profile of tumor cells. These immunosuppressive effects are reversed by IDH inhibitors recently approved for the treatments of IDH-mutant gliomas. At the same time, clinical trials have demonstrated encouraging results for targeted immunotherapies using vaccines targeting the most frequent mutation IDH1R132H.

The reversal of the immunosuppressive effects by IDH inhibitors has opened exciting avenues for combinatorial immunotherapies such as vaccines and immune checkpoint inhibitors.