Sex Bias in the Immune Response to Surgical Resection Confers a Female Survival Advantage in a Pre-Clinical Model of Glioblastoma

Introduction: Glioblastoma (GBM) is the most common primary malignant brain tumor with a median survival of less than 2 years, despite standard of care treatment: surgical resection, radiation, and chemotherapy. GBM is 1.6 times more common in males who also have a shorter overall survival. The immune system is suppressed in GBM, and studies have found sex differences in the immune response. While pre-clinical GBM models are used to interrogate GBM pathophysiology and therapeutic response, few of these models include resection, despite its role in the standard of care.

Methods: We developed a pre-clinical GBM resection model in which immunocompetent C57BL/6 or immunocompromised NSG mice were implanted with syngeneic GBM cells and underwent either resection or sham surgery to assess sex-bias in survival. Flow cytometry was used to interrogate immune phenotypes after surgery.

Results: We found that, in an immunocompetent model, female mice survived longer than male mice after surgical resection, with a median survival of 32 days compared to 24 days (p= 0.04). To determine if this difference was driven by the immune system, we repeated these assessments in immunocompromised mice and found no difference between males and females, with each group having a median survival of 15 days. Flow cytometry revealed that immunocompetent female mice who underwent resection had higher levels of immune cell infiltration in their resection cavity compared to males.

Conclusion : These results demonstrate a sex bias in survival after resection that is dependent on the immune system. The immune populations and their function will be further characterized in this model and in GBM patient samples over time to evaluate how they evolve in each sex and to identify a therapeutic target. These data underscore the complexity of sex bias in GBM and the need to account for biological sex and surgical resection in pre-clinical models to investigate next-generation therapies.