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Radiotherapy as a systemic immunomodulator, exploring the benefits of its combination with immune checkpoint inhibitors

par Cogels, Morgane
Président du jury Langer, Ingrid
Promoteur Penninckx, Sébastien
Co-Promoteur Meylan, Etienne
Publication Non publié, 2025-10-06

Thèse de doctorat

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Résumé :

Combination treatments have become the standard in cancer therapy, yet their optimization remains a challenge. Radiotherapy (RT) exhibits both anti- inflammatory and pro-inflammatory properties, with the latter offering particular promise when combined with immune checkpoint inhibitors (ICIs) to elicit systemic antitumor effects, including the abscopal effect. However, the immunomodulatory mechanisms of RT remain poorly understood and depend on factors such as dose- fractionation regimens.This thesis aimed to develop and validate a hematopoietic stem cell (HSC)- humanized NOG mouse model to investigate the immunomodulatory effects of different regimens of RT alone or combined with ICIs.As a first step, three human cancer cell lines of varying immunogenicity: renal cell carcinoma (RCC), melanoma and non-small cell lung cancer (NSCLC) were characterized in vitro by colony formation assays to assess their radiosensitivity. The hereby determined radiobiological parameters are instrumental for the interpretation of the biological effects observed in the following in vivo studies.Subsequently, HSC-humanized mice bearing RCC, melanoma or NSCLC tumors were treated with ICI, RT (2 Gy, 5 Gy, 10 Gy, or 3 x 8 Gy), or their combination (iRT). iRT significantly enhanced local tumor control and triggered abscopal effects in a regimen- and model-dependent manner. Comprehensive analyses using flow cytometry, immunohistochemistry and bulk RNA sequencing revealed the dynamic nature of the iRT-driven antitumor immune response and tumor microenvironment (TME) remodeling in both irradiated and unirradiated lesions. Late-stage responses were associated with low immune cell infiltration, immune memory features, cGAS/STING pathway activation, markers of immunogenic cell death, and metabolic reprogramming.Collectively, these findings provide new insights into the immunomodulatory role of RT and iRT, highlighting the importance of dynamic immune monitoring and supporting the use of humanized mice in iRT studies to improve translational15potential, while acknowledging their limitations. We highlight iRT as a promising strategy for both local and systemic tumor control with the occurrence of the abscopal effect under specific regimens.