Effective cancer immunotherapy appears to be dependent on creating the right inflammatory reaction at the site of the tumor. Preliminary and published data provide compelling evidence that experimentally creating a hyperthermic state, similar to that achieved during a common natural event (fever) may have the potential to augment tumor control by the immune system. The overall hypothesis of this proposal is that thermal (fever-range) stimulation of the inflammatory activity of granulocytes, or polymorphonuclear neutrophils (PMNs), helps to eliminate cancer cells in the body and is at least part of the basis by which a mild, fever-range hyperthermia helps to control tumor growth..
The specific aims of this grant proposal have been designed to obtain cellular and molecular data that will test this hypothesis and help to identity potential mechanisms by which the thermal microenvironment enhances PMN activity.
Aim 1 will utilize both syngeneic tumor models and human tumor xenograft models in mice to quantify the kinetics of hyperthermia-induced PMN localization to the tumor site. The specific contribution of PMNs to the anti-tumor effects of fever-range whole body hyperthermia (FR-WBH) will also be studied using antibody-blocking experiments and mice with PMNs that are defective in their homing function. Using various in vitro functional assays and flow cytometric analysis of activation and maturation markers, Aim 2 will then more directly test the hypothesis that FR-WBH exerts its anti-tumor effect through PMNs by increasing their migratory potential and/or increasing the overall activation status of these cells. Lastly, Aim 3 will determine whether thermally-treated PMNs exert tumoricidal activity through the production of reactive nitrogen or oxygen intermediates. Overall, this pilot research program should help to pinpoint an important role for PMNs in the effector activity of FR-WBH. Specifically, these studies will provide sufficient preliminary data for a future RO1 application that will examine even more closely the molecular mechanisms and/or signaling pathways by which fever-range temperatures regulate the PMN activities as defined in this R21 application. By obtaining a better understanding of the molecular mechanisms by which the thermal microenvironment regulates inflammatory responses, a more rational approach can be made in the use and design of future clinical trials that will utilize hyperthermia as a complimentary or alternative cancer therapy. Moreover, studies such as this can provide well-characterized cellular endpoints by which the responsiveness of individual patients to thermal therapy can be objectively measured and compared, an essential practice for validating any nature-based immunotherapy such as FR-WBH in which the responses of individuals may vary.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA098852-02
Application #
6944380
Study Section
Special Emphasis Panel (ZCA1-SRRB-Y (M1))
Program Officer
Mufson, R Allan
Project Start
2004-09-01
Project End
2007-08-31
Budget Start
2005-09-01
Budget End
2007-08-31
Support Year
2
Fiscal Year
2005
Total Cost
$230,533
Indirect Cost
Name
Roswell Park Cancer Institute Corp
Department
Type
DUNS #
824771034
City
Buffalo
State
NY
Country
United States
Zip Code
14263
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
Dayanc, Baris E; Beachy, Sarah H; Ostberg, Julie R et al. (2008) Dissecting the role of hyperthermia in natural killer cell mediated anti-tumor responses. Int J Hyperthermia 24:41-56
Capitano, Maegan L; Ertel, Bradley R; Repasky, Elizabeth A et al. (2008) Winner of the 2007 Society for Thermal Medicine Young Investigator Award. Fever-range whole body hyperthermia prevents the onset of type 1 diabetes in non-obese diabetic mice. Int J Hyperthermia 24:141-9
Ostberg, Julie R; Dayanc, Baris E; Yuan, Min et al. (2007) Enhancement of natural killer (NK) cell cytotoxicity by fever-range thermal stress is dependent on NKG2D function and is associated with plasma membrane NKG2D clustering and increased expression of MICA on target cells. J Leukoc Biol 82:1322-31
Ostberg, Julie R; Repasky, Elizabeth A (2006) Emerging evidence indicates that physiologically relevant thermal stress regulates dendritic cell function. Cancer Immunol Immunother 55:292-8
Nasirikenari, Mehrab; Segal, Brahm H; Ostberg, Julie R et al. (2006) Altered granulopoietic profile and exaggerated acute neutrophilic inflammation in mice with targeted deficiency in the sialyltransferase ST6Gal I. Blood 108:3397-405
Ostberg, Julie R; Ertel, Bradley R; Lanphere, Julie A (2005) An important role for granulocytes in the thermal regulation of colon tumor growth. Immunol Invest 34:259-72