Peptide-based PET/CT imaging visualizes PD-L1-driven radioresistance in glioblastoma.

in Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy by Yong Wang, Zhiguo Liu, Yang Li, Kelin Wang, Chunhui Yuan, Jian Shi, Jiazhong Ren, Shijie Wang, Jinping Wang, Miaoqing Zhao, Man Hu

TLDR

  • A novel peptide-based PET/CT radiotracer was developed to visualize changes in PD-L1 expression during radiotherapy for glioblastoma treatment. The radiotracer shows promise for noninvasive monitoring of PD-L1 dynamics and guiding personalized treatment strategies.
  • Key Insights: The radiotracer exhibits high specificity and binding affinity to PD-L1, and its uptake correlates positively with PD-L1 expression. The radiotracer has the potential to facilitate patient stratification and adjust radiotherapy regimens.

Abstract

Radioresistance remains a great challenge for radiotherapy in the treatment of glioblastoma (GBM). PD-L1 expression is a key contributor to radioresistance and immune escape in GBM. The lack of effective methods to monitor the change of PD-L1 during radiotherapy in patients limits timely intervention and management of the resistance. Here, we developed a novel peptide tracer [F]AlF-NOTA-PCP2 for PET/CT to visualize the changes of PD-L1 expression in response to radiotherapy, revealing PD-L1-driven radioresistance in GBM. The [F]AlF-NOTA-PCP2 demonstrated high specificity and binding affinity to PD-L1 in vitro. The uptake of [F]AlF-NOTA-PCP2 on PET/CT showed a strong positive correlation with PD-L1 expression by immunohistochemistry (IHC) (R² = 0.861, P < 0.001) in GBM xenograft tumors. The radiotracer uptake in PD-L1-positive tumors significantly increased post-radiotherapy (21.25 ± 0.91 % vs. 25.12 ± 0.82 %, P = 0.008), aligning with the radioresistance observed in these tumors. In vitro studies revealed that PD-L1-driven radioresistance by enhancing DNA damage repair through upregulation of RAD51 after activation of the PI3K-Akt pathway in cells. Preliminary clinical application in a radiotherapy-treated GBM patient demonstrated the ability to monitor PD-L1 dynamics, supporting its potential for clinical translation. Collectively, this peptide-based small molecule PET/CT radiotracers offer a noninvasive, real-time, and quantitative method to dynamically visualize PD-L1-driven radioresistance in GBM. It could serve as a potential radiotracer for facilitating patient stratification, adjusting radiotherapy regimens, and guiding personalized immunotherapy strategies.

Overview

  • This study aims to develop a novel peptide-based PET/CT radiotracer to visualize changes in PD-L1 expression during radiotherapy for glioblastoma (GBM) treatment.
  • The study uses [F]AlF-NOTA-PCP2, a peptide tracer with high specificity and binding affinity to PD-L1, to monitor PD-L1 dynamics in GBM xenograft tumors.
  • The primary objective is to develop a noninvasive method to dynamically visualize PD-L1-driven radioresistance in GBM patients, potentially facilitating personalized treatment strategies.

Comparative Analysis & Findings

  • The radiotracer uptake in PET/CT showed a strong positive correlation with PD-L1 expression by immunohistochemistry (IHC) in GBM xenograft tumors.
  • The uptake of [F]AlF-NOTA-PCP2 in PD-L1-positive tumors significantly increased post-radiotherapy, aligning with the radioresistance observed in these tumors.
  • In vitro studies revealed that PD-L1-driven radioresistance occurred through enhanced DNA damage repair via upregulation of RAD51 after activation of the PI3K-Akt pathway in cells.

Implications and Future Directions

  • The peptide-based PET/CT radiotracer offers a noninvasive, real-time, and quantitative method to dynamically visualize PD-L1-driven radioresistance in GBM patients.
  • This method could potentially be used for patient stratification, adjusting radiotherapy regimens, and guiding personalized immunotherapy strategies.
  • Future studies should investigate the clinical translation of this radiotracer and explore its application in combination with other diagnostic and therapeutic modalities.
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