Abstract
Therapeutic irradiation of the tumor microenvironment causes differential activation of pro-survival and pro-death pathways in malignant, stromal, endothelial and immune cells, hence causing a profound cellular and biological reconfiguration via multiple, non-redundant mechanisms. Such mechanisms include the selective elimination of particularly radiosensitive cell types and consequent loss of specific cellular functions, the local release of cytokines and danger signals by dying radiosensitive cells, and altered cytokine secretion by surviving radioresistant cells. Altogether, these processes create chemotactic and immunomodulatory cues for incoming and resident immune cells. Here we discuss how cytoprotective and cytotoxic signaling modules activated by radiation in specific cell populations reshape the immunological tumor microenvironment.
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Acknowledgements
We are indebted to G. Manic (Regina Elena National Cancer Institute, Rome, Italy) for help with the preparation of display items. M.E.R.R. is supported by the FEOR/CRIS Foundation. I.V. is supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC, IG 2017, grant number 20417) and a startup grant from the Italian Institute for Genomic Medicine (Turin, Italy). K.J.H. acknowledges support from the Royal Marsden/Institute of Cancer Research NIHR Biomedical Research Centre, Oracle Cancer Trust, Rosetrees Trust and The Mark Donegan Foundation. L.G. is supported by a Breakthrough Level 2 grant from the US Department of Defense, Breast Cancer Research Program (#BC180476P1); by a startup grant from the Department of Radiation Oncology at Weill Cornell Medicine (New York, US); by industrial collaborations with Lytix (Oslo, Norway) and Phosplatin (New York, US); and by donations from Phosplatin (New York, US), the Luke Heller TECPR2 Foundation (Boston, US) and Sotio a.s. (Prague, Czech Republic).
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L.G. conceived the paper. M.E.R.R., I.V. and L.G. wrote the first version of the manuscript and designed display items with inputs from K.J.H. and I.M. I.V. prepared display items under supervision from L.G. L.G. addressed comments raised by reviewers. All authors approved the final version of the article.
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I.M. receives grants form Roche, AstraZeneca, Alligator and Bristol Myers. I.M. has consulted for Bristol-Myers, Bayer, Roche, AstraZeneca, F-Star, Genmab, Seattle Genetics, Merck Serono, MSD, Alligator and Bioncotech. L.G. provides remunerated consulting to OmniSEQ, Astra Zeneca, Inzen, Boehringer Ingelheim and the Luke Heller TECPR2 Foundation, and he is member of the Scientific Advisory Committee of OmniSEQ.
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Rodriguez-Ruiz, M.E., Vitale, I., Harrington, K.J. et al. Immunological impact of cell death signaling driven by radiation on the tumor microenvironment. Nat Immunol 21, 120–134 (2020). https://doi.org/10.1038/s41590-019-0561-4
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DOI: https://doi.org/10.1038/s41590-019-0561-4
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