Hyperthermia (HT)--heating the tumor in the range of 40.0- 44.0 °C--combined with radiation (RT) and/or chemotherapy (CT) is a well proven treatment for malignant tumors. The improvement of the techniques for monitoring and adapting of the desired temperatures even in deep seated tumors has led to a renaissance of, now quality-controlled, HT in multimodal tumor therapy approaches. Randomized clinical trials have shown improved disease-free survival and local tumor control without an increase in toxicity for the combined treatment. In this review, we will focus on biological rationales of HT comprising direct cytotoxicity, systemic effects, chemosensitization, radiosensitization, and immune modulation. The latter is a prerequisite for the control of recurrent tumors and micrometastases. Immunogenic tumor cell death forms induced by HT will be introduced. Modulations of the cytotoxic properties of chemotherapeutic agents by HT as well as synergistic effects of HT with RT will be presented in the context of the main aims of anti-tumor therapy. Furthermore, modern techniques for thermal mapping like magnet resonance imaging will be outlined. The effectiveness of HT will be demonstrated by reviewing recent clinical trials applying HT in addition to CT and/or RT. We conclude that hyperthermia is a very potent radio- as well as chemosensitizer, which fosters the induction of immunogenic dead tumor cells leading to local and in special cases also to systemic tumor control.
Multimodal tumor therapies should aim not only to kill the tumor cells, but also to stimulate a specific immune response to keep residual tumor (stem) cells and metastases under control. Apoptotic cells are mostly noninflammatory or even anti-inflammatory while necrotic cells stimulate the immune system. Whether the immunogenicity of apoptotic tumor cells can be increased by interfering with their swift and phosphatidylserine (PS)-dependent clearance by macrophages was examined. AnnexinA5 (AnxA5) is a naturally occurring highly specific ligand for PS. Proteins of the annexin family are characterized by a selective affinity for phospholipids in the presence of Ca2+ ions. The phagocytosis by macrophages of irradiated, apoptotic tumor cells (ITC) was partially inhibited when the ITC were preincubated with AnxA5. Activated macrophages secreted higher amounts of TNFalpha and IL-1beta after contact with ITC plus AnxA5 in comparison with ITC alone, while the amount of TGF-beta was decreased. Macrophages of AnxA5-deficient mice showed an increased phagocytosis of dead cells. Wild-type mice, where endogenous AnxA5 is present, displayed a significantly faster decline in size of allogeneic tumors in comparison with AnxA5-deficient animals. The addition of AnxA5 to ITC vaccines increased the percentage of tumor-free mice in syngeneic tumor protection and tumor cure assays. AnxA5 alone led to a retard of syngeneic tumor growth that was, however, less pronounced in comparison to treatment of the tumor with ionizing irradiation. In conclusion, AnxA5 disturbs the PS-dependent clearance by macrophages of dying tumor cells, leading to the accumulation of the latter, to the occurrence of secondary necrotic cells, and to an increased uptake of the dead cells by dendritic cells. Tumor cure appendages with dead tumor cells should be performed with AnxA5 as an immune stimulator and could be combined with irradiation, chemotherapy, and hyperthermia to induce immunogenic cell death forms in vivo or ex vivo.
The combined treatment of colorectal tumor cells with X-ray and HT activates distinct tumor cell pathways and fosters the early appearance of a necrotic tumor cell phenotype.
Autoimmune diseases and cancer can be treated by influencing the immune system. Apo and nec cells are strong modulators of the immune system contributing to anti-inflammatory and pro-inflammatory responses, respectively. We examined which form of cell death was induced by HT and X-irradiation. Nec was the prominent form of cell death after combined treatment and the amount of dead cells was higher when exposing the cells to radiation before HT. Combined applications further led to an increased percentage of cells in a more radioresponsive G2 cell cycle phase. The danger signal HMGB1 is released when combining HT with radiation, a further hint that those treatments may induce inflammation and immune activation. We conclude that immune responses are appropriately adapted to the damage that has occurred and may contribute to anti-cancer immunity or chronic autoimmunity, respectively.
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