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Gene expression in human recurrent glioblastoma before and after inoculation with the oncolytic herpes simplex virus G207 using NanoString pancancer immune profiling gene expression panel

ABSTRACT: We have previously developed the use of genetically engineered herpes simplex virus type 1 (G207) for the experimental treatment of malignant glioma (PMID: 18957964). We demonstrated that G207 propagates in and kills nervous system tumor cells with little to no evidence of viral encephalitis. Here, six adult patients with recurrent glioblastoma were recruited onto a phase 1b clinical trial to test safety and efficacy of G207 in anti-tumor response. We obtained resected tumor tissue before and after (within 2-5 days) inoculation with G207. RNA was extracted from all tissues and subject to gene expression profiling using NanoString Pancancer Immune panel. Our data indicate in the post-G207 samples that interferon immune response and the subsequent recruitment of an adaptive immune response strongly associated with overall survival after inoculation with oncolytic virus G207 in patients with recurrent malignant glioma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE164104 | GEO | 2021/12/31

REPOSITORIES: GEO

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Project description:Low grade gliomas (LGG) account for about two-thirds of all glioma diagnoses in adolescents and young adults (AYA) and malignant progression of these patients leads to dismal outcomes. Recent studies have shown the importance of the dynamic tumor microenvironment in high-grade gliomas (HGG), yet its role is still poorly understood in low-grade glioma malignant progression. Here, we investigated the heterogeneity of the immune microenvironment using a platelet-derived growth factor (PDGF)-driven RCAS (replication-competent ASLV long terminal repeat with a splice acceptor) glioma model that recapitulates the malignant progression of low to high-grade glioma in humans and also provides a model system to characterize immune cell trafficking and evolution. To illuminate changes in the immune cell landscape during tumor progression, we performed single-cell RNA sequencing on immune cells isolated from animals bearing no tumor (NT), LGG and HGG, with a particular focus on the myeloid cell compartment, which is known to mediate glioma immunosuppression. LGGs demonstrated significantly increased infiltrating T cells, CD4 T cells, CD8 T cells, B cells, and natural killer cells in the tumor microenvironment, whereas HGGs significantly abrogated this infiltration. Our study identified two distinct macrophage clusters in the tumor microenvironment; one cluster appeared to be bone marrow-derived while another was defined by overexpression of Trem2, a known anti-tumor immunity marker in myeloid cell subpopulations. Our data demonstrates that these two distinct macrophage clusters show an immune-activated phenotype (Stat1, Tnf, Cxcl9 and Cxcl10) in LGG which evolves to an immunosuppressive state (Lgals3, Apoc1 and Id2) in HGG that restricts T cell recruitment and activation. We identified CD74 and macrophage migration inhibition factor (MIF) as potential targets for these distinct macrophage populations. Interestingly, these results were mirrored by our analysis of the TCGA dataset, which demonstrated a statistically significant association between CD74 overexpression and decreased overall survival in AYA patients with grade II LGGs. Targeting immunosuppressive myeloid cells and intra-tumoral macrophages within this therapeutic window may ameliorate mechanisms associated with immunosuppression before and during malignant progression.

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Gene expression in human recurrent glioblastoma before and after inoculation with the oncolytic herpes simplex virus G207 using NanoString pancancer immune profiling gene expression panel

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