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Krombach, J.* ; Hennel, R.* ; Brix, N.* ; Orth, M.* ; Schoetz, U.* ; Ernst, A.* ; Schuster, J.* ; Zuchtriegel, G.* ; Reichel, C.A.* ; Bierschenk, S.* ; Sperandio, M.* ; Vogl, T.* ; Unkel, S.* ; Belka, C. ; Lauber, K.

Priming anti-tumor immunity by radiotherapy: Dying tumor cell-derived DAMPs trigger endothelial cell activation and recruitment of myeloid cells.

OncoImmunology 8:e1523097 (2019)

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	Open Access Gold (Paid Option)

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The major goal of radiotherapy is the induction of tumor cell death. Additionally, radiotherapy can function as in situ cancer vaccination by exposing tumor antigens and providing adjuvants for anti-tumor immune priming. In this regard, the mode of tumor cell death and the repertoire of released damage-associated molecular patterns (DAMPs) are crucial. However, optimal dosing and fractionation of radiotherapy remain controversial. Here, we examined the initial steps of anti-tumor immune priming by different radiation regimens (20 Gy, 4 x 2 Gy, 2 Gy, 0 Gy) with cell lines of triple-negative breast cancer in vitro and in vivo. Previously, we have shown that especially high single doses (20 Gy) induce a delayed type of primary necrosis with characteristics of mitotic catastrophe and plasma membrane disintegration. Now, we provide evidence that protein DAMPs released by these dying cells stimulate sequential recruitment of neutrophils and monocytes in vivo. Key players in this regard appear to be endothelial cells revealing a distinct state of activation upon exposure to supernatants of irradiated tumor cells as characterized by high surface expression of adhesion molecules and production of a discrete cytokine/chemokine pattern. Furthermore, irradiated tumor cell-derived protein DAMPs enforced differentiation and maturation of dendritic cells as hallmarked by upregulation of co-stimulatory molecules and improved T cell-priming. Consistently, a recurring pattern was observed: The strongest effects were detected with 20 Gy-irradiated cells. Obviously, the initial steps of radiotherapy-induced anti-tumor immune priming are preferentially triggered by high single doses - at least in models of triple-negative breast cancer.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Radiotherapy ; Anti-tumor Immunity ; Abscopal Effects Of Radiotherapy ; Damps ; Endothelial Cell Activation ; Apc Recruitment ; Cancer Immunotherapy; Antigen-presenting Cells; Cd8(+) T-cells; Anticancer Chemotherapy; Molecular-mechanisms; Dendritic Cells; Radiation; Death; Cancer; Microenvironment; Differentiation

ISSN (print) / ISBN 2162-4011

e-ISSN 2162-402X

Journal OncoImmunology

Quellenangaben Volume: 8, Issue: 1, Article Number: e1523097

Publisher Taylor & Francis

Publishing Place Philadelphia

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) CCG Personalized Radiotherapy in Head and Neck Cancer (KKG-KRT)