IMMU-15. The immunologic context of pediatric central nervous system malignancies and identification of pan-histology immunomodulatory targets

Abstract

Central nervous system tumors account for the most childhood cancer mortality. Immunotherapies have made major contributions to treat adult cancers, but application of immunotherapy for childhood brain tumors has been limited, in part due to the unique CNS microenvironment and mechanisms of immune escape in this context. To investigate the immunologic context, we query the transcriptomic profile of ~700 primary brain tumors released by the Children’s Brain Tumor Network. An immune subtype classification from The Cancer Genome Atlas project reveals that 81% of high-grade tumors across molecular subtypes are characterized by an immunosuppressive phenotype (C4) while an inflammatory phenotype (C3) is more common in low-grade lesions (p<0.001). Adjusting for histologic grade and extent of resection, C4 associates with worse overall (OS) and progression-free survival (PFS) in this cohort (HR 3.1, p=0.008 and 1.6, p=0.03 respectively). Deconvolution of the transcriptome reveals that relative to C3, C4 tumors have decreased T-cell signature, OR 0.4 (0.2–0.8), and increased macrophage and tumor-proliferation signature (OR 2.0, 1.3–3.3, and 3.1, 2.3–4.2, respectively). In contrast to C3 tumors, T-cell signature in C4 tumors adversely impacts survival and correlates with multiple immunosuppressive genes and cytokines. Among them, the immune checkpoint CD276 has the highest associated impact on survival in C4 tumors (HR of log increase is 1.9, p<0.001). Additionally, high-grade lesions have suppressed expression of antigen-presenting genes. EZH2 is implicated in downregulating antigen presentation and is found to be significantly upregulated in all high-grade lesions in this cohort. Treatment with the EZH1/2 inhibitor valemetostat resulted in upregulation of antigen-presenting genes and tissue differentiation pathways across three murine syngeneic models, one modeling diffuse midline glioma and two embryonal models. Future in-vivo studies with genetic and chemical modification of immunomodulatory genes of interest aim to identify immunotherapeutic targets with potential for broad applicability in pediatric neuro-oncology.