Distinct roles of TREM2 in central nervous system cancers and peripheral cancers
Menée à l'aide de modèles murins de glioblastome ainsi que d'échantillons de gliomes et de liquides cérébrospinaux d'origine humaine, cette étude identifie, pour le récepteur TREM2 des cellules myéloïdes, des fonctions qui divergent selon le type tumoral (cancers du système nerveux central et cancers périphériques) puis met en évidence un mécanisme par lequel l'expression des récepteurs TREM2 sur les cellules myéloïdes favorise la réponse immunitaire contre les glioblastomes
Glioblastomas (GBM) are incurable central nervous system (CNS) cancers characterized by substantial myeloid cell infiltration. Whether myeloid cell-directed therapeutic targets identified in peripheral non-CNS cancers are applicable to GBM requires further study. Here, we identify that the critical immunosuppressive target in peripheral cancers, triggering receptor expressed on myeloid cells-2 (TREM2), is immunoprotective in GBM. Genetic or pharmacological TREM2 deficiency promotes GBM progression in vivo. Single-cell and spatial sequencing reveals downregulated TREM2 in GBM-infiltrated myeloid cells. TREM2 negatively correlates with immunosuppressive myeloid and T cell exhaustion signatures in GBM. We further demonstrate that during GBM progression, CNS-enriched sphingolipids bind TREM2 on myeloid cells and elicit antitumor responses. Clinically, high TREM2 expression in myeloid cells correlates with better survival in GBM. Adeno-associated virus-mediated TREM2 overexpression impedes GBM progression and synergizes with anti-PD-1 therapy. Our results reveal distinct functions of TREM2 in CNS cancers and support organ-specific myeloid cell remodeling in cancer immunotherapy.