Fractionated low-dose radiotherapy primes the tumor microenvironment for immunotherapy in a murine mesothelioma model. in Cancer immunology, immunotherapy : CII / Cancer Immunol Immunother. 2025 Jan 3;74(2):44. doi: 10.1007/s00262-024-03889-x.

2025

Tipo pubblicazione

Journal Article;

Autori/Collaboratori (7)Vedi tutti...

Cook AM
School of Physics, Mathematics and Computing, The University of Western Australia, Perth, Australia.
Nowak AK
Institute for Respiratory Health, Perth, Australia.
Ebert MA
Medical School, The University of Western Australia, Perth, Australia.

et alii...

Abstract

Combination immune checkpoint inhibitors (nivolumab and ipilimumab) are currently a first-line treatment for mesothelioma; however, not all patients respond. The efficacy of treatment is influenced by the tumor microenvironment. Murine mesothelioma tumors were irritated with various radiotherapy doses. Radiotherapy induced vasculature changes were monitored by power Doppler and photoacoustic ultrasound and analyzed via mixed-effects models. Tissue staining was used to investigate the immune cell infiltrate of tumors. The optimal radiotherapy schedule was combined with immune checkpoint inhibitors, and the survival of mice was analyzed. Using low-dose, low-fraction radiotherapy allowed favorable modification of the murine mesothelioma tumor microenvironment. Irradiating tumors with 2 Gy × 5 fractions significantly improved blood flow and reduced hypoxia, consequently increasing the presence of CD8(+) and regulatory T cells in the tumor. Understanding the transient nature of these changes is crucial for optimizing the timing of therapeutic delivery. The combination of radiotherapy with dual immunotherapy (anti-PD-1 plus anti-CTLA-4) proved highly curative when administered concurrently. A diminishing rate of cures was noted with an increasing delay between radiotherapy and subsequent immunotherapy. Concurrent low-dose, low-fraction radiotherapy emerges as a translatable approach for improving the efficacy of immune checkpoint inhibitors in patients.

PMID : 39751851

DOI : 10.1007/s00262-024-03889-x

Keywords

Combined Modality Therapy/methods; Humans; Cell Line, Tumor; Mice, Inbred C57BL; Female; Immune Checkpoint Inhibitors/therapeutic use/pharmacology; Dose Fractionation, Radiation; Disease Models, Animal; Mesothelioma/radiotherapy/immunology/therapy/pathology; Immunotherapy/methods; Tumor Microenvironment/immunology/radiation effects; Mice; Animals;