Thermal regulation of immune function and the use of heat in cancer immunotherapy

An increase in body temperature associated with inflammation or infection has been evolutionarily conserved in all cold- and warm-blooded vertebrates, and even in several invertebrates, thus far examined. This change in temperature is strongly correlated with survival from infection in many animal models. Despite these intriguing observations and significant biological sequelae, temperature manipulation is rarely considered a variable in the context of most immunological investigations.{09}We hypothesize that the thermal microenvironment can selectively regulate the immune response and that if the nature of this regulation were understood, body temperature could be manipulated as an adjuvant for cancer immunotherapy. To test this hypothesis, we examined the effect of fever-like temperatures on cytokine production by murine splenocytes and lymph node cells as well as by macrophages. We have further characterized the effects of elevated temperatures on peritoneal exudate cells by testing how heat affects their phagocytic ability, their ability to secrete immunoregulatory cytokines and their ability to produce nitric oxide via the inducible nitric oxide synthase. Finally, we have examined the role of mild hyperthermia as an adjuvant to an interleukin-12-based therapy of cancer in mice, and have begun to define the mechanism behind the efficacy of this combination treatment. The results described in this dissertation provide support for the continued examination of the biological effects of febrile temperatures on immune function and the further development of cancer immunotherapies that involve whole body heating in humans.