PD-1 inhibitor improves radiosensitivity by tumor vessel normalization.

Area of Science:

• Oncology
• Immunotherapy
• Radiotherapy

Background:

• Radiosensitivity is influenced by host immunity and tumor hypoxia.
• Anti-PD-1 immunotherapy shows potential in radiotherapy for locally advanced tumors.
• The impact of anti-PD-1 immunotherapy on radiosensitivity remains unclear.

Purpose of the Study:

• To investigate whether anti-PD-1 immunotherapy improves radiosensitivity.
• To explore the mechanisms by which anti-PD-1 immunotherapy affects radiosensitivity, including hypoxia and immune cell profiles.
• To compare induction immunotherapy with concurrent radioimmunotherapy.

Main Methods:

• In vivo mouse models (4T1 and LLC) treated with anti-PD-1 antibodies and/or X-ray irradiation.
• Bulk-RNA sequencing, flow cytometry, immunofluorescence, and hypoxia detection to analyze tumor tissues.
• Depletion of CD4+ and CD8+ T cells to assess their roles in anti-PD-1 therapy response.
• Transcriptome analysis and spatial immunophenotyping to compare treatment strategies.

Main Results:

• Induction immunotherapy mitigated hypoxia, increased radiosensitivity, and maximized anti-tumor response compared to concurrent administration.
• Anti-PD-1 therapy combined with radiotherapy significantly increased CD4+ IFNγ+ T cells compared to concurrent radioimmunotherapy.
• CD4+ T cells were crucial for PD-1 inhibitor-induced vessel normalization and hypoxia reduction.
• CD4+ T cells infiltrated tumors and localized around endothelial cells following anti-PD-1 immunotherapy.

Conclusions:

• Anti-PD-1 inhibitors enhance radiosensitivity via immune reprogramming and vascular effects.
• Vessel normalization emerges as a potential biomarker for patient selection in radiotherapy following induction immunotherapy.