Abstract
Multimodal tumor treatment settings consisting of radiotherapy and immunomodulating agents such as immune checkpoint inhibitors are more and more commonly applied in clinics. In this context, the immune phenotype of tumor cells has a major influence on the anti-tumor immune response as well as the composition of the tumor microenvironment. A promising approach to further boost anti-tumor immune responses is to add hyperthermia (HT), i.e., heating the tumor tissue between 39 °C to 45 °C for 60 min. One key technique is the use of radiative hyperthermia systems. However, knowledge is limited as to how the frequency of the used radiative systems affects the immune phenotype of the treated tumor cells. By using our self-designed in vitro hyperthermia system, we compared cell death induction and expression of immune checkpoint molecules (ICM) on the tumor cell surface of murine B16 melanoma and human MDA-MB-231 and MCF-7 breast cancer cells following HT treatment with clinically relevant microwaves at 915 MHz or 2.45 GHz alone, radiotherapy (RT; 2 × 5 Gy or 5 × 2 Gy) alone or in combination (RHT). At 44 °C, HT alone was the dominant cell death inductor with inactivation rates of around 70% for B16, 45% for MDA-MB-231 and 35% for MCF-7 at 915 MHz and 80%, 60% and 50% at 2.45 GHz, respectively. Additional RT resulted in 5–15% higher levels of dead cells. The expression of ICM on tumor cells showed time-, treatment-, cell line- and frequency-dependent effects and was highest for RHT. Computer simulations of an exemplary spherical cell revealed frequency-dependent local energy absorption. The frequency of hyperthermia systems is a newly identified parameter that could also affect the immune phenotype of tumor cells and consequently the immunogenicity of tumors.
Highlights
Cancer is the first or second leading cause of premature death in over 100 countries around the world [1]
In this work we present for the first time an ex vivo microwave heating system operating with 915 MHz which is clinically used for superficial heating of, e.g., breast wall recurrences or melanoma, and how this treatment affects the immune phenotype of tumor cells
We have developed an in vitro system to measure clinically relevant hyperthermia effects at two frequencies, 915 MHz and 2.45 GHz, and at different target temperatures, 39 ◦ C, 41 ◦ C and 44 ◦ C, alone and in combination with normo- and hypofractionation irradiation, to find out how RT in combination with HT alters the immunogenic phenotype of tumor cells and which combination is most beneficial, depending on the microwaves’ frequency
Summary
Cancer is the first or second leading cause of premature death in over 100 countries around the world [1]. Much research needs to be done to find new and better treatment options in this area, with a focus on a good cost-benefit ratio. In this context, a study by PwC predicts that per capita costs will need to decrease by approximately 6.5–27.5%. A combination of the following treatment options is commonly used: surgery, radiotherapy (RT), chemotherapy, and increasingly immunotherapy such as immune checkpoint inhibitors (ICI). Because of their high level of commitment and good results, these methods are often referred to as the four pillars of cancer treatment.
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