Hyperthermia in the febrile (> or = 41 degrees C) and therapeutic ranges (< or = 42 degrees C) may alter antitumor host defenses. Understanding the regulatory influences of hyperthermia on various host defense mechanisms will have increasing importance as BRMs use expands and we ask if hyperthermia can be used effectively with these agents. Activated monocytes/macrophages in particular appear to have great potential as effectors for BRM therapy and appropriate use of hyperthermia may enhance this potential, but the effect of hyperthermia on macrophage actions against tumor cells has not been systematically examined. We proposed to use various rodent and human sources of monocytes/macrophages and tumor cells and to study the effect of hyperthermia on various macrophage cytotoxic actions against tumor cells in vitro.
The Specific Aims are: (1) to determine if heating monocytes/macrophages alters their ability to execute various cytotoxic functions against unheated tumor cells in coculture. Conversely, does heating tumor cells alter their response to the cytotoxic actions of unheated effector cells in co-culture? (2) To ask if heated-monocyte/macrophage production of soluble cytotoxic mediators is altered, and if heating perturbs tumor cell responses to these mediators so that the net cytotoxic outcome can be optimized (3) To determine if heating monocytes/macrophages alters their ability to respond to priming and triggering signals. Conversely, does heating tumor cells activate or enhance activation of macrophages in coculture. (4) To ask if heating of monocytes/macrophages or target cells alters the selectivity of the tumoricidal reaction vis-a-vis tumor vs normal targets. (5) To determine the temporal relationships between heating of tumor cells and co- culture with monocytes/macrophages or their mediators on the cytotoxic manifestations. (6) To ask if thermotolerance protects tumor cells from monocytes/macrophages and their mediators. Conversely, can these effector cells develop thermotolerance to heat effects on their cytotoxic actions? (7) To investigate the mechanisms by which hyperthermia alters the effector cell arm of tumor necrosis factor (TNF) cytotoxic pathways. The ultimate objective of this proposal is to use answers to the above questions to help optimize the adjunctive use of hyperthermia with protocols designed to use either appropriately activated monocytes/macrophages or cytotoxic monokines in cancer therapy.
