Abstract:BackgroundRadiotherapy, administered in fractionated as well as ablative settings, is an essential treatment component for breast cancer. Besides the direct tumor cell death inducing effects, there is growing evidence that immune mechanisms contribute - at least in part - to its therapeutic success. The present study was designed to characterize the type and the extent of cell death induced by fractionated and ablative radiotherapy as well as its impact on the release of monocyte migration stimulating factors … Show more
“…This was most pronounced upon exposure to supernatants of 20 Gy-irradiated tumor cells which at the time point of supernatant collection had undergone a late-onset type of primary necrosis. 27 Similar patterns of endothelial cell and/or pericyte activation have been reported in the field of sterile inflammation with models of laser injury and hot needle injury. 42–44 Obviously, the forms of necrotic cell death which are induced by single high dose irradiation, laser injury and hot needle injury as well as the repertoire of released DAMPs share similarities, irrespective if the dying cells are malignant or not.…”
Section: Discussionsupporting
confidence: 54%
“…27 In triple-negative breast cancer cells, such as HCC1937 cells, we observed a delayed type of primary necrosis with chaotic morphology which was particularly prominent 4 days after irradiation with a high single dose of 20 Gy (Supplemental Figure 1, 27 ).10.1080/2162402X.2018.1523097-F0001Figure 1. In vivo recruitment of myeloid cell subsets stimulated by supernatants of irradiated tumor cells in an air pouch model. (a) Schematic representation of the treatment sequence in air pouch experiments.…”
Section: Resultsmentioning
confidence: 94%
“…8,35 Although nucleotides, including ATP, are released from irradiated tumor cells and stimulate chemokinetic monocyte migration in vitro , data from this and our previous study suggest that they fail to induce directional monocyte migration and do not contribute to endothelial cell activation. 27 Nevertheless, they may act as local amplifiers of recruitment signals. 46,47 …”
Section: Discussionmentioning
confidence: 99%
“…27 Obviously, different classes of DAMPs exert complementary functions, and the details of their contribution require further investigation. Within the class of protein DAMPs, we could detect high levels of HMGB1, HSP70, and S100A8/A9 in the supernatants of irradiated tumor cells.…”
Section: Discussionmentioning
confidence: 99%
“…11,27 Here, culture supernatants of these dying cells were analyzed for their effects on endothelial cell activation as well as the recruitment and activation of APCs in vitro and in vivo . The results were compared to supernatants of 4 × 2 Gy-, 2 Gy-, and sham-irradiated cells.…”
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 × 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.
“…This was most pronounced upon exposure to supernatants of 20 Gy-irradiated tumor cells which at the time point of supernatant collection had undergone a late-onset type of primary necrosis. 27 Similar patterns of endothelial cell and/or pericyte activation have been reported in the field of sterile inflammation with models of laser injury and hot needle injury. 42–44 Obviously, the forms of necrotic cell death which are induced by single high dose irradiation, laser injury and hot needle injury as well as the repertoire of released DAMPs share similarities, irrespective if the dying cells are malignant or not.…”
Section: Discussionsupporting
confidence: 54%
“…27 In triple-negative breast cancer cells, such as HCC1937 cells, we observed a delayed type of primary necrosis with chaotic morphology which was particularly prominent 4 days after irradiation with a high single dose of 20 Gy (Supplemental Figure 1, 27 ).10.1080/2162402X.2018.1523097-F0001Figure 1. In vivo recruitment of myeloid cell subsets stimulated by supernatants of irradiated tumor cells in an air pouch model. (a) Schematic representation of the treatment sequence in air pouch experiments.…”
Section: Resultsmentioning
confidence: 94%
“…8,35 Although nucleotides, including ATP, are released from irradiated tumor cells and stimulate chemokinetic monocyte migration in vitro , data from this and our previous study suggest that they fail to induce directional monocyte migration and do not contribute to endothelial cell activation. 27 Nevertheless, they may act as local amplifiers of recruitment signals. 46,47 …”
Section: Discussionmentioning
confidence: 99%
“…27 Obviously, different classes of DAMPs exert complementary functions, and the details of their contribution require further investigation. Within the class of protein DAMPs, we could detect high levels of HMGB1, HSP70, and S100A8/A9 in the supernatants of irradiated tumor cells.…”
Section: Discussionmentioning
confidence: 99%
“…11,27 Here, culture supernatants of these dying cells were analyzed for their effects on endothelial cell activation as well as the recruitment and activation of APCs in vitro and in vivo . The results were compared to supernatants of 4 × 2 Gy-, 2 Gy-, and sham-irradiated cells.…”
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 × 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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