Deciphering diffuse glioma immune microenvironment as a key to improving immunotherapy results.

Abstract

Immunotherapeutic approaches have yet to demonstrate their clinical efficacy in diffuse gliomas. Evidence is mounting that the central nervous system is subject to immune surveillance, but brain tumours manage to escape due to factors intrinsic to their tumoral immune microenvironment (TME). This review aims to discuss the recently characterized molecular bases of the glioma TME and the potentially actionable targets to improve immunotherapeutic results in these hard-to-treat cancers. Single-cell studies defined the composition of the glioma immune TME and its peculiarities compared with other solid cancers. In isocitrate dehydrogenase (IDH) wildtype gliomas, the TME is enriched in myeloid cells (monocyte-derived macrophages and resident microglia) with mainly immunosuppressive functions. Lymphocytes can infiltrate the glioma TME, but are exposed to multiple immunomodulating signals that render them in a state of deep exhaustion. IDH mutant gliomas produce the oncometabolite D-2-hydroxyglutarate with negative effects on leukocyte recruitment and function, resulting in the induction of an 'immune-desert' TME. Several molecular pathways have been recently identified in the induction of an 'immune-hostile' microenvironment in diffuse gliomas, unravelling potential vulnerabilities to targeted immunotherapies.