New preliminary and published data obtained during the last funding period has led to the novel hypothesis that the immune activity of Antigen Presenting Cells (APCs; macrophages and dendritic cells), can be stimulated by physiologically relevant thermal gradients. Because of the critical, central role these cells play in linking the innate and adaptive immune responses and in generation of long term memory responses, understanding fully the potential for APC regulation by mild (fever-range) hyperthermia could provide the essential platform of information needed for next generation protocols utilizing strategic applications of hyperthermia for the treatment of cancer. Data presented indicate that mild whole body hyperthermia speeds delayed type hypersensitivity reactions and enhances tumor control. Importantly, it also increases the production of immunostimulatory cytokines and nitric oxide and increases expression of critical cell surface molecules e.g. MHC molecules needed for activation of T lymphocytes. However, we know little about either the precise magnitude of thermal enhancement of the immune response or effects of varying the timing of its application. Further, we know very little about transcriptional/translational control of relevant genes and proteins affected by thermal stimuli. Obtaining this information is critical for rational development of new clinical protocols.
The aims of this grant will:
Aim 1) identify precisely the magnitude of the contribution of thermal stimuli administered at different times on APC function in the immune response using a well-defined antigen (ovalbumin) for which there are tools already available for dissecting the immune response, Aim 2) test the hypothesis that genes/proteins known to be involved in the immune responses defined in Aim 1 are up regulated and 3) determine transcriptional and translational processes by which thermal stimuli are able to increase production of immunostimulatory molecules (e.g., nitric oxide). Importantly, in each aim, we will use physiologically relevant APCs that infiltrate normal tissues, tumors and draining lymph nodes in mice that undergo whole body hyperthermia rather than just studying long-term cell lines, which may have lost normal thermal regulatory responses after long periods of growth in vitro. As the goals of this proposal are met and we come to understand better the biological effects of mild temperature increases on APC function, we will be able to rationally design improved clinical strategies in order to maximize the anti-tumor potential of a patient's immune response.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-CII (01))
Program Officer
Wong, Rosemary S
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Roswell Park Cancer Institute Corp
United States
Zip Code
Zynda, Evan R; Grimm, Melissa J; Yuan, Min et al. (2015) A role for the thermal environment in defining co-stimulation requirements for CD4(+) T cell activation. Cell Cycle 14:2340-54
Winslow, Timothy B; Eranki, Annu; Ullas, Soumya et al. (2015) A pilot study of the effects of mild systemic heating on human head and neck tumour xenografts: Analysis of tumour perfusion, interstitial fluid pressure, hypoxia and efficacy of radiation therapy. Int J Hyperthermia 31:693-701
Dayanc, Baris E; Bansal, Sanjay; Gure, Ali Osmay et al. (2013) Enhanced sensitivity of colon tumour cells to natural killer cell cytotoxicity after mild thermal stress is regulated through HSF1-mediated expression of MICA. Int J Hyperthermia 29:480-90
Lee, Chen-Ting; Zhong, Lingwen; Mace, Thomas A et al. (2012) Elevation in body temperature to fever range enhances and prolongs subsequent responsiveness of macrophages to endotoxin challenge. PLoS One 7:e30077
Mace, Thomas A; Zhong, Lingwen; Kokolus, Kathleen M et al. (2012) Effector CD8+ T cell IFN-? production and cytotoxicity are enhanced by mild hyperthermia. Int J Hyperthermia 28:9-18
Lee, Chen-Ting; Repasky, Elizabeth A (2012) Opposing roles for heat and heat shock proteins in macrophage functions during inflammation: a function of cell activation state? Front Immunol 3:140
Sen, Arindam; Capitano, Maegan L; Spernyak, Joseph A et al. (2011) Mild elevation of body temperature reduces tumor interstitial fluid pressure and hypoxia and enhances efficacy of radiotherapy in murine tumor models. Cancer Res 71:3872-80
Mace, Thomas A; Zhong, Lingwen; Kilpatrick, Casey et al. (2011) Differentiation of CD8+ T cells into effector cells is enhanced by physiological range hyperthermia. J Leukoc Biol 90:951-62
Beachy, Sarah H; Repasky, Elizabeth A (2011) Toward establishment of temperature thresholds for immunological impact of heat exposure in humans. Int J Hyperthermia 27:344-52
Fisher, Daniel T; Chen, Qing; Skitzki, Joseph J et al. (2011) IL-6 trans-signaling licenses mouse and human tumor microvascular gateways for trafficking of cytotoxic T cells. J Clin Invest 121:3846-59

Showing the most recent 10 out of 40 publications