SYST-27 INTERROGATION OF THE TUMOR IMMUNE MICROENVIRONMENT REVEALS DISTINCT IMMUNOSUPPRESSIVE LANDSCAPES IN GLIOBLASTOMA

Abstract

Abstract High-resolution sequencing technologies have revealed significant inter-and intra-tumoral molecular heterogeneity in glioblastoma (GBM), leading to an urgent need for novel targeted therapies. Our research using representative murine GBM models and various experimental techniques has shown that classical GBMs (e.g., EGFRvIII+, TIMElow) and mesenchymal GBMs (e.g., NF1ko/PTENko/p53ko, TIMEhigh) are both immunosuppressive but in distinct ways. TIMElow GBMs have a more impaired and less functional tumor vasculature, resulting in low infiltration of T cells with anergic features. TIMEhigh GBMs have a more intact BBB revealing overall more adaptive and innate immune cell infiltrates, but with highly dysfunctional T cells and immunosuppressive TME. Congruently, GSEA analysis of both human and murine GBM scRNA-seq data demonstrated enriched immunosuppressive signatures in the myeloid cell populations of TIMEhigh GBM compared to TIMElow GBM. Our findings have also revealed potential adaptive and intrinsic resistant mechanisms to antiangiogenic immunotherapy in TIMElow and TIMEhigh GBMs, respectively, with TIMElow GBMs exhibiting a transitory response to the treatment, while TIMEhigh GBMs being intrinsically resistant due to their intact tumor vasculature and reliance on dysfunctional T cells. We then tested the efficacy of different immunotherapies, including dendritic cell vaccination, a CD40 agonist, and a myeloid cell PI3K activity inhibitor in TIMElow and TIMEhigh tumors. Surprisingly, our results revealed that the response to these treatments can be either beneficial or detrimental and may depend on factors such as tumor antigenicity and TIME subtype. Overall, our study provides new insights into the intricate immune landscape of GBMs, emphasizes the importance of considering tumor subtypes as they may lead to potential unintended consequences of immunotherapies.