Understanding the impact of radiation-induced lymphopenia: Preclinical and clinical research perspectives

Abstract

Immunotherapy has revolutionized the field of cancer treatment, changing the standard of care to the use of immune checkpoint inhibitors. Radiotherapy can boost anti-tumour immune responses by changing the tumour microenvironment, but it also can cause radiotherapy-induced lymphopenia (RIL), a decrease in circulating lymphocyte counts. RIL has been associated with lower survival in patients undergoing radiotherapy, and new studies have suggested that it can also affect immunotherapy outcome. To study RIL's effects and to explore mitigation treatment strategies, preclinical models closely mimicking the clinical situation are needed. State-of-the-art image-guided small animal irradiators now offer the possibility to target specific organs in small animals to induce RIL, aiding research on its molecular mechanisms and prevention. This review covers the relationship between radiotherapy and RIL, its impact on patient survival, and future directions to generate models to investigate and prevent RIL.

Keywords: Immunotherapy; Preclinical models; Radiation-induced lymphopenia.

Fig. 1

Example of an irradiation plan targeting thoracic vertebrae to develop murine RIL models. (Left) Representative example of mouse chest CT image with a treatment plan designed with the software smART-ATP (SmART Scientific Solutions B.V.). Three 5 mm square beams were positioned to target the thoracic vertebrae, each consisting of two 1 Gy parallel opposed lateral beams. Dose deposition is shown by colour scale. (Right) Resulting cumulative dose-volume histogram for treatment plan depicted in left panel, indicating a maximal coverage of the target region, while a minimal dose to surrounding tissues.

Fig. 2

Strategies currently under investigation to prevent, reverse or mitigate RIL. Created with BioRender.com.

Fig. 3

Roadmap for the study of the effects of RIL on tumour progression and strategies to prevent or reverse it to improve patient survival. RT − radiotherapy; IT − immunotherapy. Created with BioRender.com.