Dying cell clearance and its impact on the outcome of tumor radiotherapy

Abstract

The induction of tumor cell death is one of the major goals of radiotherapy and has been considered to be the central determinant of its therapeutic outcome for a long time. However, accumulating evidence suggests that the success of radiotherapy does not only derive from direct cytotoxic effects on the tumor cells alone, but instead might also depend – at least in part – on innate as well as adaptive immune responses, which can particularly target tumor cells that survive local irradiation. The clearance of dying tumor cells by phagocytic cells of the innate immune system represents a crucial step in this scenario. Dendritic cells and macrophages, which engulf, process and present dying tumor cell material to adaptive immune cells, can trigger, skew, or inhibit adaptive immune responses, respectively. In this review we summarize the current knowledge of different forms of cell death induced by ionizing radiation, the multi-step process of dying cell clearance, and its immunological consequences with special regard toward the potential exploitation of these mechanisms for the improvement of tumor radiotherapy.

Consensus guidelines for the detection of immunogenic cell death

“…36,37 Upon binding to low density lipoprotein receptorrelated protein 1 (LRP1, also known as CD91), membraneexposed CALR delivers a major phagocytic signal to professional antigen-presenting cells (APCs) such as dendritic cells, de facto improving their capacity to take up dead cells and their corpses. 66,91,[166][167][168][169][170][171][172][173] Interestingly, the phagocytosis-stimulatory effects of CALR is robustly counterbalanced by CD47, which is highly expressed by a large panel of solid and hematopoietic tumors. 166 This latter observation suggests that various neoplasms benefit from avoiding the effects of CALR exposure, perhaps as this prevents the elicitation of an adaptive immune response against the malignant cells that "physiologically" succumb in the course of oncogenesis and tumor progression.…”

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

“…7–10 However, the mode of cell death induced by ionizing irradiation is not uniform, and it clearly depends on the irradiation dose, the fractionation regimen, and the genetic repertoire of the irradiated cells. 3,10 Proliferating cells of the hematopoietic system predominantly undergo apoptosis upon irradiation, as characterized by externalization of phosphatidylserine, membrane blebbing, chromatin condensation, and DNA fragmentation, while the integrity of the plasma membrane remains intact. 11 If apoptotic cells are not removed in time by professional or non-professional phagocytes, they progress into secondary, post-apoptotic necrosis: The integrity of the plasma membrane collapses, and intracellular contents, including DAMPs, are released.…”

“…11 If apoptotic cells are not removed in time by professional or non-professional phagocytes, they progress into secondary, post-apoptotic necrosis: The integrity of the plasma membrane collapses, and intracellular contents, including DAMPs, are released. 3,12 In cells of epithelial origin, the extent of apoptosis induction upon irradiation is rather limited. As long as cell cycle checkpoint function is maintained, epithelial cells exit the cell cycle into cellular senescence as hallmarked by upregulation of cyclin-dependent kinase inhibitors, such as p16, p21, and p27, and expression of senescence-associated β-galactosidase.…”

Cross-Presentation of the Oncofetal Tumor Antigen 5T4 from Irradiated Prostate Cancer Cells—A Key Role for Heat-Shock Protein 70 and Receptor CD91

“…High-dose (10-100 Gy) in vitro irradiation of tumor cells enhances CRT translocation to the cell surface and dose-dependent release of HMGB1 and ATP by breast, colon, and prostate cancer cell lines (13). These typical ICD markers may facilitate phagocytosis of damaged/dead cells and provide maturation signals for DCs (14).…”