Exosome‐transmitted podoplanin promotes tumor‐associated macrophage‐mediated immune tolerance in glioblastoma

Published:12 March 2024 DOI: 10.1111/cns.14643 PMID: 38470096

Mengwan Wu, Ying Shi, Yuyang Liu, Hongxiang Huang, Jiajia Che, Jing Shi, Chuan Xu

Abstract

Aims

Glioblastoma is the most frequent and aggressive primary brain tumor, characterized by rapid disease course and poor treatment responsiveness. The abundance of immunosuppressive macrophages in glioblastoma challenges the efficacy of novel immunotherapy.

Methods

Bulk RNA-seq and single-cell RNA-seq of glioma patients from public databases were comprehensively analyzed to illustrate macrophage infiltration patterns and molecular characteristics of podoplanin (PDPN). Multiplexed fluorescence immunohistochemistry staining of PDPN, GFAP, CD68, and CD163 were performed in glioma tissue microarray. The impact of PDPN on macrophage immunosuppressive polarization was investigated using a co-culture system. Bone marrow-derived macrophages (BMDMs) and OT-II T cells isolated from BALB/c and OT-II mice respectively were co-cultured to determine T-cell adherence. Pathway alterations were probed through RNA sequencing and western blot analyses.

Results

Our findings demonstrated that PDPN is notably correlated with the expression of CD68 and CD163 in glioma tissues. Additionally, macrophages phagocytosing PDPN-containing EVs (EVs^PDPN) from GBM cells presented increased CD163 expression and augmented secretion of immunoregulatory?cytokine (IL-6, IL-10, TNF-α, and TGF-β1). PDPN within EVs was also associated with enhanced phagocytic activity and reduced MHC II expression in macrophages, compromising CD4⁺ T-cell activation.

Conclusions

This investigation underscores that EVs^PDPN derived from glioblastoma cells contributes to M2 macrophage-mediated immunosuppression and is a potential prognostic marker and therapeutic target in glioblastoma.