Mouse models are used heavily in aging research and the results of these experiments are used to predict differences in anti-tumor immunity and efficacy of immunotherapy between young and aged humans. Recent work from our laboratory has demonstrated that thermoregulatory challenges arising from cool housing conditions mandated for mouse research colonies have had an unrecognized impact on our attempts to understand the anti-tumor capabilities of the immune response of young mice, particularly the balance between anti-tumor effector cells and pro-tumorigenic immunosuppressive cells. Interestingly, for aged mice, there is considerable evidence that physiological changes associated with aging include impaired thermoregulation. Therefore aged mice are more sensitive to cold than young mice. However, to date, the relationships between tumor growth, chronic cold stress, thermal preference and anti-tumor immunity have not been investigated in aged mice. The major goal of this R03 application is to extend our analysis of the impact of housing temperature to aged tumor bearing mice, and determine whether aged tumor bearing mice may have an even more profound immunosuppressive response to chronic cold stress than do young mice. Here, we hypothesize that the inability of aged mice, which already face thermoregulatory challenges, to deal sufficiently with the additional cold stress imposed by housing temperatures is skewing the outcome of fundamental mouse research on aging and anti-cancer immunity.
Two specific aims are proposed to address this hypothesis:
Aim 1) To determine how growth rates of several different tumor models are influenced by ambient temperature in aged mice and to conduct thermal preference tests to determine whether the preferred ambient temperature of aged, tumor bearing, mice differs from that seen in young mice and Aim 2) To evaluate the balance between effector T cells and immunosuppressive cells, as well as the expression of selected cytokines/chemokines in aged naive and tumor bearing mice as a function of ambient temperature and compare to data obtained from young animals. Obtaining an accurate baseline understanding of the ability of older mice to develop anti-tumor immunity, and understanding how thermoregulatory stress may impact this ability in comparison to young mice is critical to the interpretation of experiments investigating the immune response in aged mice and ultimately for the development of clinically successful immunotherapies. This R03 application will answer, in a short time frame, the focused question of how aged tumor bearing mice are influenced by standard housing temperature, a situation which could be interfering with our full understanding of their responses to immunotherapy and other therapies.
Our lab has recently demonstrated that data obtained from young mice used to study cancer growth and anti-tumor immunity are being influenced by the high degree of thermoregulatory, adrenergic stress caused by the cool housing temperature required in mouse research facilities. We propose here to extend our analysis to determine (for the first time) the effect this has on tumor growth in aged mice, and to assess the specific impact on anti-tumor immunity. Obtaining information on baseline differences in the degree of cold stress experienced by young and aged mice is highly significant because of the importance of pre-clinical testing of immunotherapy efforts for young as well as aged individuals.
| Bucsek, Mark J; Qiao, Guanxi; MacDonald, Cameron R et al. (2017) ?-Adrenergic Signaling in Mice Housed at Standard Temperatures Suppresses an Effector Phenotype in CD8+ T Cells and Undermines Checkpoint Inhibitor Therapy. Cancer Res 77:5639-5651 |
| Hylander, Bonnie L; Repasky, Elizabeth A (2016) Thermoneutrality, Mice, and Cancer: A Heated Opinion. Trends Cancer 2:166-175 |
