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 5

Dexamethasone broadly reverses the LPS-induced inflammatory transcriptional program in iPSC-derived microglia, including cytokine expression and Hallmark inflammatory pathway activation.

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Dexamethasone broadly reverses the LPS-induced inflammatory transcriptio...
(A) Schematic of the iPSC-derived microglial experiment. iPSCs were differentiated into microglia before being treated for 24 hours. RNA was then extracted from the cells. Differential gene expression analysis was performed. (B) Venn diagram representing the number of unique and overlapping differentially expressed (P adj < 0.05) genes in each comparison. (C) The addition of dexamethasone to LPS reversed the expression of a large number of genes that were initially differentially expressed with LPS. The number of overlapping genes that were differentially expressed in opposite directions in the LPS vs. CTRL and LPS+dexamethasone vs. LPS comparisons was significantly greater than would be expected by chance (P < 1 × 10−10, hypergeometric test). (D) Dexamethasone broadly reversed a large number of cytokines that were upregulated with the addition of LPS. The log2(FC) column represents the log fold-change in expression between the LPS and LPS+dexamethasone conditions. An asterisk (*) next to a gene name denotes that LPS induced a significant change in expression that was significantly reversed in the LPS+dexamethasone condition. (E) LPS induced a broad upregulation of Hallmark inflammatory genes, which were relatively downregulated when cells were treated with a combination of LPS+dexamethasone. (F–H) Normalized RNA expression for Il1b, Il6, and Tnf.