Convection-enhanced delivery of dexamethasone in glioma models suppresses myeloid inflammation while avoiding systemic toxicities
Nathaniel W. Rolfe, Nicholas B. Dadario, Liang Lei, Anthony J. Tang, Misha Amini, Damian E. Teasley, Nkechime Ifediora, Peter J. Chabot, Nathan J. Winans, Nina Yoh, Julia Furnari, Corina Kotidis, Clara H. Stucke, Nivia M. Urena, Yanping Sun, Abby L. Brand, Ashwin Viswanathan, Pavan Upadhyayula, Michael G. Argenziano, Colin P. Sperring, Nadine Khoury, Nelson Humala, Shikun Wang, Justin Neira, Peter A. Sims, Brian J.A. Gill, Peter Canoll, Jeffrey N. Bruce
Nathaniel W. Rolfe, Nicholas B. Dadario, Liang Lei, Anthony J. Tang, Misha Amini, Damian E. Teasley, Nkechime Ifediora, Peter J. Chabot, Nathan J. Winans, Nina Yoh, Julia Furnari, Corina Kotidis, Clara H. Stucke, Nivia M. Urena, Yanping Sun, Abby L. Brand, Ashwin Viswanathan, Pavan Upadhyayula, Michael G. Argenziano, Colin P. Sperring, Nadine Khoury, Nelson Humala, Shikun Wang, Justin Neira, Peter A. Sims, Brian J.A. Gill, Peter Canoll, Jeffrey N. Bruce
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Research Article Inflammation Oncology

Convection-enhanced delivery of dexamethasone in glioma models suppresses myeloid inflammation while avoiding systemic toxicities

Abstract

Dexamethasone is widely used to control cerebral edema and inflammation in glioblastoma, but its benefits are limited by systemic toxicities and adverse prognostic associations. We evaluated local administration of dexamethasone via convection-enhanced delivery (CED) to maximize intratumoral antiinflammatory effects by increasing local corticosteroid exposure while minimizing systemic exposure. In 2 glioma mouse models, continuous intraparenchymal infusion of dexamethasone was well tolerated with no adverse effects. Pharmacokinetic analyses supported preferential intratumoral distribution and reduced systemic exposure with CED compared with systemic dosing. Single-nucleus RNA sequencing and immunohistochemistry showed attenuation of glioma-associated inflammation with downregulation of reactive microglial/macrophage programs and reduced tumor-infiltrating myeloid cells with a morphology consistent with a less activated state. Experiments in human induced pluripotent stem cell–derived microglia confirmed that dexamethasone directly suppresses inflammatory gene expression, indicating a conserved mechanism across species. This inflammatory suppression was recapitulated in both immortalized microglial (HMC3) and macrophage (THP-1) cell lines. These findings suggest that localized dexamethasone delivered by CED reprograms the glioma immune microenvironment and achieves control of inflammation without the systemic adverse effects associated with standard systemic dexamethasone therapy. This clinically translatable strategy may improve symptom management and provide a platform for integrating local immunomodulation with future glioblastoma therapies.

Authors

Nathaniel W. Rolfe, Nicholas B. Dadario, Liang Lei, Anthony J. Tang, Misha Amini, Damian E. Teasley, Nkechime Ifediora, Peter J. Chabot, Nathan J. Winans, Nina Yoh, Julia Furnari, Corina Kotidis, Clara H. Stucke, Nivia M. Urena, Yanping Sun, Abby L. Brand, Ashwin Viswanathan, Pavan Upadhyayula, Michael G. Argenziano, Colin P. Sperring, Nadine Khoury, Nelson Humala, Shikun Wang, Justin Neira, Peter A. Sims, Brian J.A. Gill, Peter Canoll, Jeffrey N. Bruce

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Figure 4

CED-dexamethasone suppresses inflammatory myeloid programs in glioma, reduces IBA1/MSR1-associated myeloid cells, and promotes a less activated morphology.

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CED-dexamethasone suppresses inflammatory myeloid programs in glioma, re...
(A) Tumors were implanted on DPI 0. On DPI 21, mice received CED-dexamethasone (100 ng/μL), systemic dexamethasone (10 mg/kg daily i.p.), or vehicle. After 7 days of treatment, mice were euthanized for snRNA-seq or histology. (B) UMAP of myeloid nuclei showing macrophage-like (Msr1+, Cd74+) and microglial-like (P2ry12+, Tmem119+) clusters. (C) CED-dexamethasone reduced immune activation gene expression in myeloid nuclei. (D) Hallmark GSEA showed inflammatory and immune-related pathways enriched in vehicle-treated mice and suppressed after CED-dexamethasone, including IL-6, IL-1β, and TNF-α signaling. (E) In TCGA and CGGA GBM cohorts, above-median expression of the 50 most downregulated myeloid genes following CED-dexamethasone was associated with worse overall survival (P = 0.0018). (F) Representative immunofluorescence images showing ionized calcium-binding adapter molecule 1 (IBA1) positivity in CRE-positive tumor fields; scale bar: 20 μm. (G) IBA1-positive area was decreased in dexamethasone-treated tumors (CTRL vs. SYS, P = 0.018; CTRL vs. CED, P = 0.0031; CED vs. SYS, P = 0.031). (H) IBA1-positive area remained reduced with CED-dexamethasone after normalization to total cellularity as a proxy for tumor burden (P < 0.0001). (I) Representative immunofluorescence images showing IBA1 and MSR1 in the tumor core; scale bar: 20 μm. (J) CED-dexamethasone reduced MSR1-positive cells versus control (P = 0.0032); systemic dexamethasone showed a nonsignificant trend (P = 0.24). (K) Representative ramified and ameboid myeloid cell; scale bar: 5 μm. (L) Morphological analysis showed that CED-dexamethasone made tumor-associated IBA1-positive cells less spherical and more branched; statistics computed per cell. Statistical differences were analyzed using Kruskal-Wallis test followed by post hoc t test (H, I, and K). (*P < 0.05; **P < 0.01, ***P < 0.001, ****P < 0.0001.)