Abstract
Simple SummaryRadio-sensitizing effects of moderate or mild hyperthermia (heating up tumor cells up to 41–43 °C) in combination with radiotherapy (thermoradiotherapy) have been evaluated for decades. However, how this combination might modulate an anti-tumor immune response is not well known. To investigate the dynamic behavior of immune–tumor ecosystems in different scenarios, a model representing an artificial adaptive immune system in silico is used. Such a model may be far removed from the real situation in the patient, but it could serve as a laboratory to investigate fundamental principles of dynamics in such systems under well-controlled conditions and it could be used to generate and refine hypothesis supporting the design of clinical trials. Regarding the results of the presented computer simulations, the main effect is governed by the cellular radio-sensitization. In addition, the application of hyperthermia during the first radiotherapy fractions seems to be more effective.There is some evidence that radiotherapy (RT) can trigger anti-tumor immune responses. In addition, hyperthermia (HT) is known to be a tumor cell radio-sensitizer. How HT could enhance the anti-tumor immune response produced by RT is still an open question. The aim of this study is the evaluation of potential dynamic effects regarding the adaptive immune response induced by different combinations of RT fractions with HT. The adaptive immune system is considered as a trainable unit (perceptron) which compares danger signals released by necrotic or apoptotic cell death with the presence of tumor- and host tissue cell population-specific molecular patterns (antigens). To mimic the changes produced by HT such as cell radio-sensitization or increase of the blood perfusion after hyperthermia, simplistic biophysical models were included. To study the effectiveness of the different RT+HT treatments, the Tumor Control Probability (TCP) was calculated. In the considered scenarios, the major effect of HT is related to the enhancement of the cell radio-sensitivity while perfusion or heat-based effects on the immune system seem to contribute less. Moreover, no tumor vaccination effect has been observed. In the presented scenarios, HT boosts the RT cell killing but it does not fundamentally change the anti-tumor immune response.
Highlights
Preclinical and, to some extent, clinical research demonstrated that radiotherapy (RT)is able to modulate anti-tumor immune responses [1,2,3,4]
The idea of activating the immune system by radiation leads to the question of how hyperthermia (HT) in combination with
The artificial immune–tumor ecosystem proposed by Scheidegger et al [33] consists of two major components: a tumor ecosystem, including host tissue and immune cells in the tumor compartment, and a perceptron [35] for antigen pattern recognition (Figure 1)
Summary
Preclinical and, to some extent, clinical research demonstrated that radiotherapy (RT)is able to modulate anti-tumor immune responses [1,2,3,4]. Regarding the tissue level, increased perfusion leading to a removal of acidic metabolites [13,14,15] and re-oxygenation [16,17,18] have been discussed by several authors. Re-oxygenation is known as a radio-sensitizing factor [19,20], but the effect of, e.g., combining 3–6 of total 32 fractions of RT with HT may be very limited [21], especially when considering time gaps between application of HT and RT of 30–120 or more minutes in clinical routine treatments. The wash-out of acidic metabolites by increased perfusion below 42–43 ◦ C could improve the immune system response [22,23,24,25]
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