Nanoparticle-mediated blockade of CXCL12/CXCR4 signaling enhances glioblastoma immunotherapy: Monitoring early responses with MRI radiomics.
Acta Biomater
; 177: 414-430, 2024 03 15.
Article
em En
| MEDLINE
| ID: mdl-38360292
ABSTRACT
The limited therapeutic efficacy of checkpoint blockade immunotherapy against glioblastoma is closely related to the blood-brain barrier (BBB) and tumor immunosuppressive microenvironment, where the latter is driven primarily by tumor-associated myeloid cells (TAMCs). Targeting the C-X-C motif chemokine ligand-12/C-X-C motif chemokine receptor-4 (CXCL12/CXCR4) signaling orchestrates the recruitment of TAMCs and has emerged as a promising approach for alleviating immunosuppression. Herein, we developed an iRGD ligand-modified polymeric nanoplatform for the co-delivery of CXCR4 antagonist AMD3100 and the small-molecule immune checkpoint inhibitor BMS-1. The iRGD peptide facilitated superior BBB crossing and tumor-targeting abilities both in vitro and in vivo. In mice bearing orthotopic GL261-Luc tumor, co-administration of AMD3100 and BMS-1 significantly inhibited tumor proliferation without adverse effects. A reprogramming of immunosuppression upon CXCL12/CXCR4 signaling blockade was observed, characterized by the reduction of TAMCs and regulatory T cells, and an increased proportion of CD8+T lymphocytes. The elevation of interferon-γ secreted from activated immune cells upregulated PD-L1 expression in tumor cells, highlighting the synergistic effect of BMS-1 in counteracting the PD-1/PD-L1 pathway. Finally, our research unveiled the ability of MRI radiomics to reveal early changes in the tumor immune microenvironment following immunotherapy, offering a powerful tool for monitoring treatment responses. STATEMENT OF SIGNIFICANCE:
The insufficient BBB penetration and immunosuppressive tumor microenvironment greatly diminish the efficacy of immunotherapy for glioblastoma (GBM). In this study, we prepared iRGD-modified polymeric nanoparticles, loaded with a CXCR4 antagonist (AMD3100) and a small-molecule checkpoint inhibitor of PD-L1 (BMS-1) to overcome physical barriers and reprogram the immunosuppressive microenvironment in orthotopic GBM models. In this nanoplatform, AMD3100 converted the "cold" immune microenvironment into a "hot" one, while BMS-1 synergistically counteracted PD-L1 inhibition, enhancing GBM immunotherapy. Our findings underscore the potential of dual-blockade of CXCL12/CXCR4 and PD-1/PD-L1 pathways as a complementary approach to maximize therapeutic efficacy for GBM. Moreover, our study revealed that MRI radiomics provided a clinically translatable means to assess immunotherapeutic efficacy.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Contexto em Saúde:
6_ODS3_enfermedades_notrasmisibles
Problema de saúde:
6_brain_nervous_system_cancer
Assunto principal:
Benzilaminas
/
Glioblastoma
/
Nanopartículas
/
Ciclamos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Acta Biomater
/
Acta biomater
/
Acta biomaterialia
Ano de publicação:
2024
Tipo de documento:
Article