TMIC-55. Tumor mRNA delivery via microgel-chemokine-mRNA (MCM) complex reprograms microglia and induces glioma regression through CCL4-CCR5 axis
Year: 2025
Type: article
Abstract: INTRODUCTION To overcome immunosuppressive tumor microenvironment (TME) in GBM, our group developed ‘onion-like’ mRNA clusters in a microgel–chemokine matrix for enhanced immunogenicity. Instead of lipid particle localization to antigen presenting cells, this microgel-chemokine-mRNA (MCM) complex recruits dendritic and natural killer cells forming an ectopic Th1 lymph node necessary for educating and sustaining intra-tumoral immunotherapy. The objective of this study was to evaluate the effect of vaccine for GBM. METHODS C57BL/6 mice underwent intracranial implantation of KR158-luc tumor cells and underwent SQ injection of the MCM vaccine using total tumor mRNA. Tumors were harvested at defined time points for flow cytometry and transcriptomic profiling. Bulk RNA-seq was performed to characterize differential gene expression and pathway enrichment. Flow cytometry was done to evaluate the CCR5 expression (receptor for CCL4) in the TME. RESULTS MCM treatment significantly upregulated CCL4 within the tumor, and blockade of CCL4 abrogated the survival benefit conferred by the vaccine. Flow cytometry revealed that microglia in the TME had the highest expression of the CCR5 receptor. Bulk RNA-seq revealed a distinct transcriptional profile in the MCM-treated group, including enrichment of pathways related to T cell activation, cytokine signaling, and leukocyte migration. These findings suggest MCM drives adaptive immune activation and T cell migration in the TME. Gene ontology (GO) analysis indicated a shift toward M1-like microglial activation, with upregulation of pro-inflammatory mediators such as TNF, IL-6, and CD86. Next, QPCR on the isolated microglia from TME revealed MCM induces a pronounced shift toward the M1 pro-inflammatory microglial phenotype, characterized by increased expression of pro-inflammatory cytokine markers. CONCLUSION MCM treatment drives potent anti-tumor immunity in GBM by reprogramming microglia toward a pro-inflammatory phenotype and promoting T cell activation and infiltration within the TME.
Source: Neuro-Oncology
Authors: Ravi Kumar, Anjali Chauhan, Farhad Dastmalchi, Vignesh Subramaniam, Thomas E Angelini, Jeffrey K Harrison, Kyle McGrath, Changlin Yang, Nagheme Thomas, Gregory P Takacs, Grace Hey, Chloe DeYoung, Macaulay Y Tomdio, Olivia R Packham, Ghaidaa Ebrahim, Neel N Patel, Oriana Cristina Otero, Maryam Imran, Niccolo A Rugger, Ziqi Cui, Maha Hashmi, Dingpeng Zhang, Anna DeVries, Hamza Syed, Christine von Roemeling, Loic Deleyrolle, Jianping Huang, Duane A Mitchell, Hector Gomez-Mendez, Elias J Sayour, Maryam Rahman
Institution: University of Florida
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4416139720
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