P02.09.B SURGICAL RESECTION OF GLIOBLASTOMA INDUCES IMMUNOSUPPRESSION

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Abstract BACKGROUND Glioblastoma (GB) is one of the deadliest cancers, recurring at a rate of 90%, despite a high standard of care composed of gross total surgery, fractioned and concomitant chemoradiation, and adjuvant chemotherapy. Moreover, numerous immunotherapies have not succeeded in enhancing survival rates for GB patients. GBs are known for having an immunosuppressive tumor microenvironment (TME); nonetheless, only a limited number of studies have explored the biological alterations that occur in the TME following surgical interventions. MATERIAL AND METHODS In this study, we established novel syngeneic mouse models for stereotaxic fluorescence-guided surgical resection of the GB. We performed multi-omics analyses (single-cell RNA-seq and bulk proteomics) combined with digital pathology to better understand the short-term molecular dynamics in the TME after surgery. RESULTS We discovered that surgery gave rise to ischemic and necrotic areas within the residual tumor even far from the surgical cavity. This led to remodeling of the TME with hypoxic pathways induced in all TME components. Hypoxia induced immunosuppression at multiple levels. Post-surgical immunosuppression was characterized by reshuffling of the GB immune TME. Surgery induced a decrease in the number of immunoactive cells, such as T and B cells, as well as dendritic cells, and an increase in their immunosuppressive counterparts, such as hypoxic macrophages, or Tregs. We also observed a transient increase of neutrophils. These changes were associated with an increase in immunosuppressive pathways, such as Ctla4 in T cells or Spp1 in myeloid cells, and a decrease in immune-activating pathways, such as interferon pathways. Consistent with these findings, we observed a transcriptomic reduction in antigen presentation within vascular, myeloid, and GB cells, as well as a decrease in immunoglobulins, as revealed by proteome analysis. Notably, the cell-to-cell interactions between the TME and GB cells changed radically. The hypoxic TME, such as vascular cells, hypoxic macrophages, and neutrophils, actively interacted with tumor cells, thus re-shaping the tumor towards an immunosuppressed environment. CONCLUSION Overall, our results showed that although surgery is a crucial procedure for improving the survival of patients with GB, it induces immunosuppression, which may lead to glioblastoma resistance to conventional therapy and immunotherapy.

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