ID #559 Pediatric low-grade gliomas exhibit enrichment of a TIM-3+, immunosuppressed myeloid cell population

Abstract

Pediatric low-grade gliomas (pLGGs), driven by MAPK pathway alterations, are the most common brain tumors in children, characterized by slow-growing tumors with a high survival rate but significant morbidity. pLGGs exhibit pronounced immune cell infiltration, particularly by microglia. We previously identified high expression of the immune checkpoint receptor TIM-3 and its ligand Galectin-9 in pLGG-associated myeloid cells, suggesting a potential role of immune suppression in pLGG tumors.

Publicly available scRNA-seq datasets (n = 3) from pLGG tumors (n = 41 samples in total) were analyzed. Myeloid cells were stratified into TIM-3high (z-score >1) and TIM-3low (z-score < -1) populations for pseudobulk differential gene expression and GO-term enrichment analyses. scRNA-seq data from healthy developing cortex (n = 12 samples) were used as controls. An in vitro co-culture model using iPSC-derived microglia (iMG) and patient-derived pLGG cell lines is currently being established to functionally investigate TIM-3 signaling.

scRNA-seq data showed higher proportions of TIM-3+ myeloid cells (pLGG: 41±13.2% vs. cortex: 29.1±14%), Galectin-9+ myeloid cells (36.7±14.3% vs. 7.9±6.4%), and TIM-3+/Galectin-9+ myeloid cells (18.4±9.6% vs. 2.2±2%) in pLGGs compared to healthy cortex. Furthermore, GO-term analysis revealed a downregulation of immune-related processes, including antigen processing and presentation, positive regulation of immune response, and phagocytosis, in TIM-3high versus TIM-3low myeloid cell populations in pLGGs.

The increased prevalence of TIM-3–expressing myeloid cells in pLGGs suggests tumor-driven recruitment of TIM-3+ cells or induction of TIM-3 following recruitment. Furthermore, the reduced immune activation signatures in TIM-3high cells indicate an immunosuppressive role for TIM-3 signaling in pLGG. Taken together, these findings suggest that targeting TIM-3 may represent a promising immunotherapeutic strategy for pLGG. Further elucidation of TIM-3 function in pLGG-associated myeloid cells, including through experimental studies using preclinical models such as the iMG–pLGG co-culture model, is needed to provide a rationale for immunotherapy in pLGGs.