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  3. Nanoparticle-mediated blockade of CXCL12/CXCR4 signaling enhances glioblastoma immunotherapy: Monitoring early responses with MRI radiomics

Nanoparticle-mediated blockade of CXCL12/CXCR4 signaling enhances glioblastoma immunotherapy: Monitoring early responses with MRI radiomics

  • Acta Biomater. 2024 Feb 13:S1742-7061(24)00067-9. doi: 10.1016/j.actbio.2024.02.007.
Ruili Wei 1,  Jiamin Li 2,  Wanxian Lin 3,  Xinrui Pang 4,  Huikang Yang 5,  Shengsheng Lai 6,  Xinhua Wei 7,  Xinqing Jiang 8,  Youyong Yuan 9,  Ruimeng Yang 10
Affiliations

Affiliations

  • 1 School of Medicine, South China University of Technology, Guangzhou 510006, PR China; Department of Radiology, the Second Affiliated Hospital, South China University of Technology, Guangzhou 510180, PR China. Electronic address: mcruiliwei@mail.scut.edu.cn.
  • 2 School of Medicine, South China University of Technology, Guangzhou 510006, PR China; Department of Radiology, the Second Affiliated Hospital, South China University of Technology, Guangzhou 510180, PR China. Electronic address: mc1719452379@mail.scut.edu.cn.
  • 3 School of Medicine, South China University of Technology, Guangzhou 510006, PR China; Department of Radiology, the Second Affiliated Hospital, South China University of Technology, Guangzhou 510180, PR China. Electronic address: 202220157577@mail.scut.edu.cn.
  • 4 School of Medicine, South China University of Technology, Guangzhou 510006, PR China; Department of Radiology, the Second Affiliated Hospital, South China University of Technology, Guangzhou 510180, PR China. Electronic address: archer_8558@163.com.
  • 5 School of Medicine, South China University of Technology, Guangzhou 510006, PR China; Department of Radiology, the Second Affiliated Hospital, South China University of Technology, Guangzhou 510180, PR China. Electronic address: eyyanghk@scut.edu.cn.
  • 6 School of Medical Equipment, Guangdong Food and Drug Vocational College, Guangzhou 510520, PR China. Electronic address: laiss@gdyzy.edu.cn.
  • 7 School of Medicine, South China University of Technology, Guangzhou 510006, PR China; Department of Radiology, the Second Affiliated Hospital, South China University of Technology, Guangzhou 510180, PR China. Electronic address: eyxinhuawei@scut.edu.cn.
  • 8 School of Medicine, South China University of Technology, Guangzhou 510006, PR China; Department of Radiology, the Second Affiliated Hospital, South China University of Technology, Guangzhou 510180, PR China. Electronic address: eyjiangxq@scut.edu.cn.
  • 9 School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou 511442, PR China. Electronic address: yuanyy@scut.edu.cn.
  • 10 School of Medicine, South China University of Technology, Guangzhou 510006, PR China; Department of Radiology, the Second Affiliated Hospital, South China University of Technology, Guangzhou 510180, PR China. Electronic address: eyruimengyang@scut.edu.cn.
PMID: 38360292 DOI: 10.1016/j.actbio.2024.02.007
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.

Keywords

CXCL12/CXCR4 signaling; MRI radiomics; blood-brain barrier; glioblastoma; immunosuppressive microenvironment.

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