Modern Radiotherapy Concepts and the Impact of Radiation on Immune Activation

Language
en
Document Type
Article
Issue Date
2017-10-09
Issue Year
2016
Authors
Deloch, Lisa
Derer, Anja
Hartmann, Josefin
Frey, Benjamin
Fietkau, Rainer
Gaipl, Udo S.
Editor
Abstract

Even though there is extensive research carried out in radiation oncology, most of the clinical studies focus on the effects of radiation on the local tumor tissue and deal with normal tissue side effects. The influence of dose fractionation and timing particularly with regard to immune activation is not satisfactorily investigated so far. This review, therefore, summarizes current knowledge on concepts of modern radiotherapy (RT) and evaluates the potential of RT for immune activation. Focus is set on radiation-induced forms of tumor cell death and consecutively the immunogenicity of the tumor cells. The so-called non-targeted, abscopal effects can contribute to anti-tumor responses in a specific and systemic manner and possess the ability to target relapsing tumor cells as well as metastases. The impact of distinct RT concepts on immune activation is outlined and pre-clinical evidence and clinical observations on RT-induced immunity will be discussed. Knowledge on the radiosensitivity of immune cells as well as clinical evidence for enhanced immunity after RT will be considered. While stereotactic ablative body radiotherapy seem to have a beneficial outcome over classical RT fractionation in pre-clinical animal models, in vitro model systems suggest an advantage for classical fractionated RT for immune activation. Furthermore, the optimal approach may differ based on the tumor site and/or genetic signature. These facts highlight that clinical trials are urgently needed to identify whether high-dose RT is superior to induce anti-tumor immune responses compared to classical fractionated RT and in particular how the outcome is when RT is combined with immunotherapy in selected tumor entities.

The primary goal of radiotherapy (RT) in cancer therapy is to eliminate the disease by restricting the reproductive potential of tumor cells. This is achieved by the induction of tumor cell death as well as the inhibition of the proliferating capacity of the cells (1). RT is a valuable therapy that is able to control tumor growth, eliminate the tumor, reduce the risk of cancer recurrence, and ultimately to improve survival (2). Radiation predominantly induces DNA damage in the cells (3) and some of its most prominent consequences are apoptosis, necrosis, mitotic catastrophe (MC), autophagy, cell cycle arrest, and/or senescence (Figure 1). About 60% of patients with solid tumors receive RT [15% RT monotherapy, 45% radiochemotherapy (RCT)], making it the most common treatment option for cancer (4, 5). Recent advances in radiation technologies have opened the field for new and promising radiation strategies, such as the stereotactic ablative body radiotherapy (SABR). However, while it has become generally accepted that RT is capable of inducing anti-tumor immunity (6), little is known about the effects of particular high-dose RT on the immune system. In this review, we will, therefore, deal with radiation-induced cell responses, current state-of-the-art radiation protocols, as well as the direct or indirect impact of fractionation schemes and radiation doses on the cells of the immune system, including limitations and draw-backs of today’s radiation research.

Journal Title
Frontiers in Oncology
Volume
6
Citation
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