Immuno-radiotherapy enhances tumor control and induces abscopal responses in a humanized mouse model.
Radiation therapy (RT) offers a tool to enhance immune checkpoint inhibitor (ICI) efficacy, yet its immunomodulatory potential remains poorly understood. Here, we investigated how RT dose-fractionation regimens shape local and systemic antitumor immunity.
A hematopoietic stem cell-humanized NOG mouse model was established, bearing ICI-responsive renal cell carcinoma (RCC) or ICI-resistant non-small cell lung cancer (NSCLC) and melanoma. Mice were treated with RT using different dose-fractionation regimens in combination with ICI. Tumor growth, systemic immune responses, and abscopal effects were assessed. Immune remodeling was characterized by flow cytometry, immunohistochemistry, and RNA-sequencing analyses.
Immuno-RT (iRT) improved tumor control across models, and induced abscopal effects in ICI-resistant models, especially in NSCLC, where 3x8 Gy combined with ICI triggered systemic responses, increased circulating monocytes and remodeled the tumor microenvironment (TME). Late-stage responses in ICI-resistant tumors were marked by low immune infiltration but enriched signatures of immune memory, cGAS/STING pathway, damage associated molecular patterns, cell death, and metabolic reprogramming. Our findings support RT as a strategy to overcome ICI resistance and validate humanized mice as a translational model for iRT research.
A hematopoietic stem cell-humanized NOG mouse model was established, bearing ICI-responsive renal cell carcinoma (RCC) or ICI-resistant non-small cell lung cancer (NSCLC) and melanoma. Mice were treated with RT using different dose-fractionation regimens in combination with ICI. Tumor growth, systemic immune responses, and abscopal effects were assessed. Immune remodeling was characterized by flow cytometry, immunohistochemistry, and RNA-sequencing analyses.
Immuno-RT (iRT) improved tumor control across models, and induced abscopal effects in ICI-resistant models, especially in NSCLC, where 3x8 Gy combined with ICI triggered systemic responses, increased circulating monocytes and remodeled the tumor microenvironment (TME). Late-stage responses in ICI-resistant tumors were marked by low immune infiltration but enriched signatures of immune memory, cGAS/STING pathway, damage associated molecular patterns, cell death, and metabolic reprogramming. Our findings support RT as a strategy to overcome ICI resistance and validate humanized mice as a translational model for iRT research.
Authors
Cogels Cogels, Serra Serra, Duvillier Duvillier, Garaud Garaud, Verset Verset, Venet Venet, Iliadi Iliadi, de Bakker de Bakker, Buisseret Buisseret, Rouas Rouas, Sotiriou Sotiriou, Rothé Rothé, de Caluwé de Caluwé, Van Gestel Van Gestel, Penninckx Penninckx
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