Next Steps for Immunotherapy in Glioblastoma

Cao, Toni; Wainwright, Derek A.; Lee-Chang, Catalina; Miska, Jason; Sonabend, Adam M.; Heimberger, Amy B.; Lukas, Rimas V.

doi:10.3390/cancers14164023

Cited by 10 publications

(8 citation statements)

References 202 publications

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“…Tumor-immune system interplay in GBM is complex, which hinder the development of immunotherapies (Cao et al 2022). One of important findings in our study that loss of TET2 function enhanced PD-L1 expression stimulated by IFN-γ, enabling GBM cells to flight with antitumor immunity together with lowering the effectiveness of anti-PD-L1 therapy.…”

Section: Discussionmentioning

confidence: 76%

MiR-10b-5p Impairs TET2-Mediated Inhibition of PD-L1 Transcription Thus Promoting Immune Evasion and Tumor Progression in Glioblastoma

Chen

et al. 2023

Tohoku J. Exp. Med.

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Objective: Glioblastoma (GBM) is a highly aggressive primary brain tumor that shows intratumoral heterogeneity at the cellular and molecular level. Activation of programmed death receptor 1(PD-1) interaction with its ligand PD-L1 is a well-known mechanism requisite for immune evasion deployed by malignant tumors including GBM. Herein, we set out to dissect the mechanism explaining the regulation of PD-L1 gene expression in GBM. Methods:The clinical samples consisted of 37 GBM tissues and 18 normal brain tissues. GBM cell model was treated by microRNA (miRNA) inhibitor, DNA constructs, and siRNAs. Assays of CCK-8 and Transwell insert were employed to assess the survival, migratory and invasive ability of GBM cell model. The immunosuppressive factor production, T cell apoptosis, and T cell cytotoxicity to GBM cells were evaluated in the co-culture system.Results: GBM exhibited more miR-10b-5p abundance than normal at both tissue and cellular level. Suppression of miR-10b-5p weakened the ability of GBM cell model to survive, migrate, and invade, decreased the release of immunosuppressive factors, reduced T cell apoptosis, and strengthened the T cell cytotoxicity to GBM cell model. miR-10b-5p conferred a negative control of TET2 that was downregulated in GBM. The functions of miR-10b-5p on GBM cell aggressiveness and immune evasion were mediated by TET2. TET2 recruited histone deacetylases HDAC1 and HDAC2 into the PD-L1 promoter region thus inhibiting its transcription. Conclusion:The study demonstrated the importance of miR-10b-5p-mediated repression of TET2 in PD-L1-driven immune evasion and their potential for immunotherapeutic targeting in GBM.

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Section: Discussionmentioning

confidence: 76%

MiR-10b-5p Impairs TET2-Mediated Inhibition of PD-L1 Transcription Thus Promoting Immune Evasion and Tumor Progression in Glioblastoma

Chen

et al. 2023

Tohoku J. Exp. Med.

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“…Then the normalized matrix of these cells was extracted using the function GetAssayData() with the option slot set to “data”. These files were used as input for COMET 15 to identify the significant markers that distinguish each immunomodulatory program.…”

Section: Methodsmentioning

confidence: 99%

“…Immunotherapy has revolutionized treatment for many types of cancer. Unfortunately, despite anecdotal responses 12,13 , immunotherapy trials have failed to provide life-prolonging benefit for glioma patients 14,15 . Gliomas represent an immunotherapy challenge due to the unique immune microenvironment of the brain, restricted access of systemic therapies due to the blood-brain barrier, and the need to balance therapeutic immune responses with potentially fatal inflammation-induced edema.…”

Section: Introductionmentioning

confidence: 99%

Programs, Origins, and Niches of Immunomodulatory Myeloid Cells in Gliomas

Miller,

Farran,

Couturier

et al. 2023

Preprint

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Gliomas are incurable malignancies notable for an immunosuppressive microenvironment with abundant myeloid cells whose immunomodulatory properties remain poorly defined. Here, utilizing scRNA-seq data for 183,062 myeloid cells from 85 human tumors, we discover that nearly all glioma-associated myeloid cells express at least one of four immunomodulatory activity programs: Scavenger Immunosuppressive, C1Q Immunosuppressive, CXCR4 Inflammatory, and IL1B Inflammatory. All four programs are present in IDH1 mutant and wild-type gliomas and are expressed in macrophages, monocytes, and microglia whether of blood or resident myeloid cell origins. Integrating our scRNA-seq data with mitochondrial DNA-based lineage tracing, spatial transcriptomics, and organoid explant systems that model peripheral monocyte infiltration, we show that these programs are driven by microenvironmental cues and therapies rather than myeloid cell type, origin, or mutation status. The C1Q Immunosuppressive program is driven by routinely administered dexamethasone. The Scavenger Immunosuppressive program includes ligands with established roles in T-cell suppression, is induced in hypoxic regions, and is associated with immunotherapy resistance. Both immunosuppressive programs are less prevalent in lower-grade gliomas, which are instead enriched for the CXCR4 Inflammatory program. Our study provides a framework to understand immunomodulatory myeloid cells in glioma, and a foundation to develop more effective immunotherapies.

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“…[4] Currently, significant efforts have been made to develop immunotherapies that regulate the immune response of peripheral lymphocytes (such as macrophages, dendritic cells (DCs) or T cells) against malignant glioma. [5] Unfortunately, these widely accepted immunotherapies have hardly achieved the anticipated clinical efficacy due in part to the challenges of getting peripheral immune cells into the brain, which lacks lymphatic drainage and presents the blood-brain barrier (BBB). [6] In addition, although some bone marrowderived macrophages could be recruited to malignant glioma during the tumor initiation, the macrophages-targeted therapies, such as modulation of macrophage M1/M2 polarization, showed limited efficacy in clinical trials due to tumor microenvironment (TME)-mediated acquired resistance.…”

Section: Introductionmentioning

confidence: 99%

Enhancement of Microglia Functions by Developed Nano‐Immuno‐Synergist to Ameliorate Immunodeficiency for Malignant Glioma Treatment

Cheng

Meng

et al. 2023

Adv Healthcare Materials

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Resident microglia are key factors in mediating immunity against brain tumors, but the microglia in malignant glioma are functionally impaired. Little immunotherapy has been explored to restore microglial function against glioma. Herein, oleanolic acid (OA) (microglia “restorer”) and DPPA‐1 peptide (immune checkpoint blockade) were integrated on a nano‐immuno‐synergist (DPAM@OA) to work coordinately. The self‐assembled OA core was coated with macrophage membrane for efficient blood‐brain barrier penetration and microglia targeting, on which DPPA‐1 peptide was attached via acid‐sensitive bonds for specific release in tumor microenvironment. With the enhanced accumulation of the dual drugs in their respective action sites, DPAM@OA effectively promoted the recruitment and activation of effector T cells by inhibiting aberrant activation of STAT‐3 pathway in microglia, and assisted activated effector T cells in killing tumor cells by blocking elevated immune checkpoint proteins in malignant glioma. Eventually, as adjuvant therapy, the rationally designed nano‐immuno‐synergist hindered malignant glioma progression and recurrence with or without temozolomide. Our work demonstrates the feasibility of a nano‐formulation for microglia‐based immunotherapy, which may provide a new direction for the treatment of brain tumors.This article is protected by copyright. All rights reserved

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Next Steps for Immunotherapy in Glioblastoma

Cited by 10 publications

References 202 publications

MiR-10b-5p Impairs TET2-Mediated Inhibition of PD-L1 Transcription Thus Promoting Immune Evasion and Tumor Progression in Glioblastoma

MiR-10b-5p Impairs TET2-Mediated Inhibition of PD-L1 Transcription Thus Promoting Immune Evasion and Tumor Progression in Glioblastoma

Programs, Origins, and Niches of Immunomodulatory Myeloid Cells in Gliomas

Enhancement of Microglia Functions by Developed Nano‐Immuno‐Synergist to Ameliorate Immunodeficiency for Malignant Glioma Treatment

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