Modulation of the ATP-adenosine signaling axis combined with radiotherapy facilitates anti-cancer immunity in brain metastasis

Salamero-Boix, A.; Schulz, M.; Anthes, J.; Mayer, J.; Moeckl, A.; Tsoukala, I.; Menger, D.; Mosa, M.; Hetzer, J.; Macas, J.; Hehlgans, S.; Schuck, J.; Roller, B.; Reiss, Y.; Hochart, G.; Bonnel, D.; Medyouf, H.; Rodriguez, M. B.; Broggini, T.; Czabanka, M.; Plate, K. H.; Heikenwaelder, M.; Roedel, F.; Harter, P. N.; Imkeller, K.; Sevenich, L.

doi:10.1101/2024.09.30.615883

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bioRxiv · 10.1101/2024.09.30.615883

Modulation of the ATP-adenosine signaling axis combined with radiotherapy facilitates anti-cancer immunity in brain metastasis

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Abstract

The immunosuppressive microenvironment in the brain poses a major limitation to successful therapy for brain metastases. Here we report that blockade of the ATP-to-adenosine-converting enzymes CD39 and CD73 and the adenosine receptor A2AR in combination with radiotherapy attenuates tumor progression in a breast-to-brain metastasis model by facilitating anti-cancer immunity. Immunophenotyping revealed loss of exhausted T cells and higher abundance of anti-cancer effector T cell populations. This effect was accompanied by a decrease of immunosuppressive lipid-laden macrophages and an expansion of CD14CD33high macrophages associated with antigen presentation. Analyses of human brain metastases samples supports a role of the ATP-adenosine signaling axis in modulating tumor inflammation and identified expression of CD39 and adenosine deaminase as predictive markers for patient survival and/or immune infiltration. Our findings demonstrate that the adenosine axis represents a druggable pathway to achieve local immunomodulation and treatment response, opening a new therapeutic avenue for brain metastases patients.

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Salamero-Boix, A., Schulz, M., Anthes, J., Mayer, J., Moeckl, A., Tsoukala, I., Menger, D., Mosa, M., Hetzer, J., Macas, J., Hehlgans, S., Schuck, J., Roller, B., Reiss, Y., Hochart, G., Bonnel, D., Medyouf, H., Rodriguez, M. B., Broggini, T., Czabanka, M., Plate, K. H., Heikenwaelder, M., Roedel, F., Harter, P. N., Imkeller, K., Sevenich, L.. 2024-10-02. Modulation of the ATP-adenosine signaling axis combined with radiotherapy facilitates anti-cancer immunity in brain metastasis. https://doi.org/10.1101/2024.09.30.615883

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