Abscopal, immunological effects of radiotherapy: Narrowing the gap between clinical and preclinical experiences

Abstract

SummaryRadiotherapy-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. K E Y W O R D Sabscopal effect, anti-tumor immunity, immunogenic cell death, radiotherapy | INTRODUCTIONTogether with surgery and chemotherapy, radiotherapy (RT) plays a central role in oncological treatment regimens. More than 60% of all cancer patients receive RT at one point during their medical attendance. 1 Traditionally, the efficacy of RT has been exclusively credited to its ability to induce cancer cell death and the notion that tumors are more prone to damage induced by ionizing radiation (IR) than non-malignant, normal tissues. According to the concept of the four R's of radiotherapy, repair (of IR-induced damage), reoxygenation, redistribution (to other cell cycle phases), and regeneration are the major determinants of a tissue's response toward IR.2 Importantly, tumors and non-malignant tissues are considered to differ in these characteristics, thus forming the rationale for the use of fractionated irradiation regimens with daily fractions over a period of 3-6 weeks in the clinical routine.It needs to be stressed that in the majority of all cases RT is applied in local settings with a high degree of spatial precision and the cardinal aim to achieve locoregional tumor control. However, there is accumulating evidence that-although applied locally-RT can induce systemic anti-tumor responses leading to regression and rejection of non-irradiated, distant tumor lesions. Collectively, these observations have been summarized under the term 'abscopal effects of RT', and meanwhile it is well accepted that immune mechanisms are the underlying driving forces. For distinct chemotherapeutics, the induction of such systemic, immune-mediated effects has been extensively analyzed by the groups of G. Kroemer and L. ZitvogeI....

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

“…38 Meanwhile, it is well acknowledged that anti-tumor immune mechanisms can be stimulated by radiotherapy in the sense of an in situ cancer vaccination. 4,6 However, the optimal dosing and fractionation regimen for the induction of anti-tumor immunity by ionizing irradiation remain controversial. 21,39–41 …”

“…2–4 Apart from tumor antigens which need to be made accessible to the immune system, the presence of adjuvants orchestrating the recruitment, differentiation, and activation of antigen-presenting cells (APCs) in the tumor microenvironment is of pivotal importance for the successful priming of anti-tumor immunity. 5,6 In this regard, tumor cells undergoing immunogenic forms of cell death are known to release damage-associated molecular patterns (DAMPs), including heat shock protein 70 (HSP70), high mobility group box1 (HMGB1), and ATP, thereby supporting the recruitment and maturation of APCs. 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.…”

“…10,14 In parallel to the different modes of cell death, the induction of systemic immune responses by local radiotherapy – known as radiotherapy’s abscopal effects – varies widely with the model systems and the radiation regimen employed. 6,15–17 Investigations in different mouse tumor models revealed that radiotherapy-induced anti-tumor immune reactions, which are essentially dependent on type-I interferons (produced by the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) axis), APCs, and cytotoxic CD8 + T cells, are exclusively stimulated by high single doses (10–20 Gy). 18–23 On the contrary, a recent study suggests that 3 × 8 Gy may be optimal.…”

Checkpoint Inhibitors in Head and Neck Cancer: Current Knowledge and Perspectives

“…In the R/M setting, pembrolizumab alone or in combination with fluorouracil/platinum versus the SOC, that is, EXTREME trial regimen (cetuximab+platinum+5-FU) is currently being investigated in a phase III trial (NCT02358031) and results are eagerly awaited. Furthermore, synergy between ICI and RT, both inside and outside of the radiation field (known as an abscopal effect) has been documented in different tumors in both mouse models and in humans 33. Exposure of cancer cell neoantigens following radiation-induced cell death leads to priming of T cells, which can in turn cause tumor regression in distant sites outside of radiation field, potentiated by the action of checkpoint inhibitors.…”

Combination of Immunotherapy and Brain Radiotherapy in Metastatic Melanoma: A Retrospective Analysis

“…This hypothesis may explain the so-called abscopal effect, that is, the evidence of disease response at nonirradiated sites during RT in patients with systemic malignancies. Abscopal effect can be observed in hematological tumors, but some cases have been described also in solid cancers including MM [11-13]. Given the contradictory evidence regarding this topic, we aimed to investigate the potential interaction between brain RT and IO in a single-institution cohort of patients with MM.…”