Females experience a greater benefit from surgical resection in an immune-dependent manner in a preclinical glioblastoma model

Abstract Background Glioblastoma (GBM) is 1.6 times more common in males, who also have a shorter survival. Recent evidence has demonstrated sex differences in the immune response to GBM. While preclinical models are often used to interrogate GBM, resection is often not performed, despite its role in standard of care. It is also unclear how biological sex impacts outcome after resection in preclinical models. Methods To address this question, we developed a preclinical resection model in which mice were implanted with syngeneic GBM cells and underwent tumor resection. RNA sequencing was used to characterize transcriptional changes, immune phenotype was investigated via flow cytometry, and patient outcomes were analyzed using the National Cancer Database. Results In an immunocompetent model, females survived longer than males post-resection. The survival bias favoring females was abrogated in immunocompromised mice, suggesting an immune-mediated mechanism for prolonged survival in female mice. After resection, immunocompetent female mice had higher immune cell infiltration in the resection cavity, and males had notably decreased regulatory T cells (Tregs). Correspondingly, when Tregs were depleted in both male and female mice, the sex bias was abrogated. Finally, GBM patients did not display a survival sex bias post-biopsy, but in patients who underwent resection, females survived longer. Conclusions These results demonstrate an immune-dependent sex bias in survival post-resection and suggest that Tregs may serve a protective role for survival post-operatively. These data underscore the complexity of sex bias and the immune response in GBM and the need to account for biological sex and resection in preclinical models to investigate next-generation therapies.