Pancreatic ductal adenocarcinoma (PDAC) is a highly devastating disease with poor prognosis and rising incidence. Late detection and a particularly aggressive biology are the major challenges which determine therapeutic failure. In this review, we present the current status and the recent advances in PDAC treatment together with the biological and immunological hallmarks of this cancer entity. On this basis, we discuss new concepts combining distinct treatment modalities in order to improve therapeutic efficacy and clinical outcome – with a specific focus on protocols involving radio(chemo)therapeutic approaches.

Lung, breast, and esophageal cancer represent three common malignancies with high incidence and mortality worldwide. The management of these tumors critically relies on radiotherapy as a major part of multi-modality care, and treatment-related toxicities, such as radiation-induced pneumonitis and/or lung fibrosis, are important dose limiting factors with direct impact on patient outcomes and quality of life. In this review, we summarize the current understanding of radiation-induced pneumonitis and pulmonary fibrosis, present predictive factors as well as recent diagnostic and therapeutic advances. Novel candidates for molecularly targeted approaches to prevent and/or treat radiation-induced pneumonitis and pulmonary fibrosis are discussed.

Summary: Radiotherapy—despite being a local therapy that meanwhile is characterized by an impressively high degree of spatial accuracy—can stimulate systemic phenomena which occasionally lead to regression and rejection of non‐irradiated, distant tumor lesions. These abscopal effects of local irradiation have been observed in sporadic clinical case reports since the beginning of the 20th century, and extensive preclinical work has contributed to identify systemic anti‐tumor immune responses as the underlying driving forces. Although abscopal tumor regression still remains a rare event in the radiotherapeutic routine, increasing numbers of cases are being reported, particularly since the clinical implementation of immune checkpoint inhibiting agents. Accordingly, interests to systematically exploit the therapeutic potential of radiotherapy‐stimulated systemic responses are constantly growing. The present review briefly delineates the history of radiotherapy‐induced abscopal effects and the activation of systemic anti‐tumor immune responses by local irradiation. We discuss preclinical and clinical reports with specific focus on the corresponding controversies, and we propose issues that should be addressed in the future in order to narrow the gap between preclinical knowledge and clinical experiences.

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.

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.