Figure 1.

Challenges for immunotherapy in IDH-mutant low-grade gliomas. LGG are immunologically “cold” and poorly infiltrated by immune cells due to the following reasons: They usually have an intact blood-brain barrier that is composed of the endothelial cells, their basement membrane, the perivascular space, and the astrocyte endfeet that form the glia limitans and hinders homing of the immune cells into the brain parenchyma. LGG have mutant IDH 1/2 enzymes leading to the generation of 2-hydroxygluatrate, which suppresses (⊥) T cell activity. Additional alterations in the tryptophan metabolism have been identified, inducing immunosuppressive myeloid states via kynurenine. Furthermore, tumor-derived small extracellular vesicles have been suggested to inhibit effector T cell and NK cell activity (↓) and increase the infiltration of Tregs (↑). Beyond that, preclinical studies have observed that IDH-mutation is associated with less immunoreactive microglia. However, the exact mechanism must be determined. Moreover, while LGG have a low mutational burden, a high level of inter- and intra-patient heterogeneity has been observed, making it challenging to design antigen-specific therapies.