IMMU-46. Sex-Based Immune Divergence in Glioblastoma Correlates with Distinct T Cell States and Survival Outcomes

Abstract Glioblastoma (GBM) exhibits notable sex disparities, with males experiencing a higher incidence and reduced survival compared to females. These disparities are likely attributable to hormonal, genetic, and behavioral factors, with sex-specific immune regulation potentially influencing disease progression and treatment outcomes. Sex-biased immune responses are observed in autoimmune and infectious diseases, and preclinical studies have demonstrated that male mice exhibit a stronger response to anti-PD-1 therapy while possessing more exhausted T-cells. In this study, we employed clinical, peripheral, and tumor-based multi-omics immune profiling to discern sex-specific immune patterns in patients with GBM. RNA sequencing of peripheral blood T cells indicated a heightened immune activation capacity in female patients, characterized by increased expression of interferon-gamma (IFN-γ), CD69, and ICOS. Conversely, male patients exhibited significantly elevated levels of inhibitory immune markers, including BTLA. Furthermore, multicolor flow cytometry of PBMCs revealed a more naïve T cell repertoire in females, whereas males demonstrated increased frequencies of CD8+ effector memory and early effector-like T cells, along with higher expression of exhaustion-associated checkpoint molecules, such as PD-1, indicating a more exhaustion-prone immune phenotype in males. Additionally, females showed elevated expression of the purinergic marker, CD73, suggesting divergent pathway engagement. Complementing transcriptomic and cytometric data, proteomic analysis of soluble immune mediators revealed reduced levels of key proinflammatory cytokines and chemokines, including IL1RL2, IL17A, CCL7, and CSF3, in male patients. Moreover, tumor-intrinsic immune signatures derived from gene expression and methylation data corroborated these sex-related differences. Males exhibited significantly higher expression of the inhibitory and angiogenesis-associated marker, endothelin receptor type B (EDNRB). Additionally, elevated LAG3 expression was associated with poorer overall survival in male patients exclusively. Clinically, high peripheral neutrophil counts were correlated with increased MRI FLAIR volume and poor overall survival in males, but not in females, further supporting sex-specific differences in tumor–immune interactions and clinical outcomes.