Characterizing the Myeloid Microenvironment in IDH-Mutant Gliomas

Introduction: Isocitrate dehydrogenase (IDH) mutant gliomas are the most prevalent primary CNS malignancy in young adults, but little is known about how the immune landscape differs between IDH-mutant and wildtype tumors. The aim of this study is to characterize the myeloid tumor microenvironment (TME) in IDH-mutant glioma patients and assess its prognostic implications.

Methods: RNA data from 656 gliomas from the CGGA and 662 gliomas from TCGA were analyzed via CIBERSORT immune profiling. CIBERSORT profiling was used to compare immune signatures with overall survival (OS). To better understand what might be driving the enrichment scores of pre-defined macrophage signatures, we performed immunohistochemistry (IHC) on biopsies from patients with high- and low-grade IDH-mutant tumors. Biopsies were stained, and the myeloid cell population was characterized using Iba1, MSR1, and P2RY12. Iba1 was chosen as a pan-myeloid marker, MSR1 as a pathologic macrophage marker, and P2RY12 as a homeostatic myeloid marker.

Results: In both genome databases, an elevated enrichment score in a specific subset of macrophages correlated with significantly worse OS in IDH-mutant patients (p < 0.001), but not in IDH-wildtype patients when controlling for other prognostic factors. IHC analysis showed an increased MSR1 labeling index in high-grade compared to low-grade IDH-mutant tumors (p=0.02). Iba1 labeling trended toward an inverse correlation with OS when adjusted for tumor grade (p=0.11). Additionally, MSR1 and P2RY12 indices were anticorrelated (p=0.026).

Conclusion : RNA sequencing suggests that IDH-mutant gliomas have a unique myeloid-based RNA expression pattern that correlates with survival that is not seen in wildtype tumors. IHC revealed variability in Iba1-positive infiltrate among IDH-mutant patients which may correlate with OS. Increased MSR1 in high-grade, IDH-mutant tumors may point to increased trafficking of bone marrow-derived macrophages to the TME. Additional studies are needed to validate the CIBERSORT macrophage signatures and better understand the unique myeloid TME in IDH-mutant gliomas.