Abstract IA21: Impact of thermoregulatory metabolism on immunosuppression and therapeutic responsiveness of tumors

Abstract

Abstract An important, but underappreciated, aspect of using mouse models in cancer research concerns the impact of basic housing conditions on mouse physiology and how this influences what we have come to consider “baseline” responses. In fact, we recently published data (Kokolus et al., PNAS, 2013; Kokolus et al., Front. Imm. 2014) demonstrating the surprising influence of mild cold stress (resulting from standard, IACUC-enforced housing temperatures) on tumor growth rates, CD8+T cell and dendritic cell function, and the degree of immunosuppressive cell activity which together show that the anti-tumor immune response in control mice is significantly suppressed. Newer data (N. Leigh/K. Kokolus et al., see separate abstract at this meeting) has revealed that mild cold stress also significantly influences the severity of graft vs. host disease (GVHD) in major mouse models of bone marrow transplantation, a condition which also depends upon the balance between effector T cell function and immunosuppressive activity which apparently can be easily shifted by thermoregulatory stress. These and other data, including our observations that intrinsic therapeutic sensitivity of tumor cells is significantly influenced by housing temperature (J. Eng et al., submitted; see separate abstract at this meeting), are disconcerting in terms of revealing the degree to which the outcomes of mouse experimentation can be influenced by these variables which are rarely recognized. However, it has also been fortuitous as we have begun to appreciate intriguing relationships between thermoregulatory metabolism and immune cell activity which, if understood more completely, could be exploited to improve immunotherapy for cancer or other diseases. Mild cold stress stimulates the production of norepinephrine by the sympathetic nervous system which in turn stimulates metabolic heat production via thermogenesis in brown fat and other tissues. This talk will focus on our recognition that increased β-adrenergic signaling by norepinephrine in mildly cold-stressed mice is a key event, driving not only changes in anti-tumor immunity, but also but therapeutic responsiveness in mouse tumor models, as well as the observed differences in GVHD. Excitingly, treatment of mice with common β−blockers largely reverses the phenotypes associated with mild cold stress in each of these models. Overall, these data support the idea that systemic stress is a significant variable that should be considered when evaluating therapies in mouse tumor models or for evaluating the impact of metabolism on the immune response. Alleviating this stress may identify novel targets for improving cancer therapies, and in particular, immunotherapies, in patients. Citation Format: Elizabeth A. Repasky. Impact of thermoregulatory metabolism on immunosuppression and therapeutic responsiveness of tumors. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr IA21.