title: Effects of thermal stress on tumor antigenicity and recognition by immune effector cells.
abstract: The primary rationale for the application of clinical hyperthermia in the therapy of cancer is based on the direct cytotoxic effect of heat and the radio-chemosensitization of tumor cells. More recently, additional attention is given to the observation that heat and heat-shock proteins can activate the host's immune system. The expression of heat-shock genes and proteins provides an adaptive mechanism for stress tolerance, allowing cells to survive non-physiologic conditions. However, the same adaptive mechanism can ultimately favor malignant transformation by interfering with pathways that regulate cell growth and apoptosis. Cytoprotection and thermotolerance raised the concern that heat-treated tumor cells might also be resistant to attack by immune effector mechanisms. Many studies, including those from our group, address this concern and document that heat-exposure, although transiently modulating sensitivity to CTL, do not hinder CTL attack. Moreover, there are promising reports of heat-related upregulation of NK-activating ligands, rendering those tumors which have lost MHC class I molecules target for NK cell attack. Heat-induced cytoprotection, therefore, does not necessarily extend protection from cytotoxic immune mechanisms. When interpreting the effects of heat, it is important to keep in mind that thermal effects on cell physiology are strongly dependent on the thermal dose, which is a function of the magnitude of change in temperature and the duration of heat exposure. The thermal dose required to induce cell death in vitro strongly varies from cell type to cell type and depends on microenvironmental factors (Dewey 1994). Therefore, to dissect the immunological behaviour of a given tumor and its micro-environment at different thermal doses, it is essential to characterize the thermosensitivity of every single tumor type and assess the proportion of cells surviving a given heat treatment. In this review, we summarize the pleiotropic effects that heat exposure has on tumor cells. In particular, we focus on the effects of heat on the antigen presentation of tumor cells and their susceptibility to immune effector mechanisms. We emphasize that the response to thermal stress is not a one-time point event, but rather a time period starting with the heat exposure and extending over several days of recovery. In addition, the response of tumor cells and their susceptibility to immune effector cells is strongly dependent on the model system, on the magnitude and duration of the thermal stress and on the time of recovery after heat exposure. Consideration of these aspects might help to explain some of the conflicting results that are reported in the field of thermal stress response.
authors.affiliation: Clinical Cooperation Group on Hyperthermia, Internal Medicine Department III, Klinikum Grosshadern, Ludwig-Maximilians-University, Marchioninistrasse 15, 81377, Munich, Germany. Valeria.bruehl-milani@med.uni-muenchen.de
authors.forename: Valeria
authors.initials: V
authors.lastname: Milani
authors.forename: Elfriede
authors.initials: E
authors.lastname: Noessner
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D006360:Heat-Shock Proteins / Q000276:immunology*; D006358:Hot Temperature; D006801:Humans; D006979:Hyperthermia, Induced; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy; D013312:Stress, Physiological / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D006360:Heat-Shock Proteins